S23 Concomitant , parasites and immune responses

F. E. G. COX* Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK

 Concomitant infections are common in nature and often involve parasites. A number of examples of the interactions between protozoa and viruses, protozoa and bacteria, protozoa and other protozoa, protozoa and helminths, helminths and viruses, helminths and bacteria, and helminths and other helminths are described. In mixed infections the burden of one or both the infectious agents may be increased, one or both may be suppressed or one may be increased and the other suppressed. It is now possible to explain many of these interactions in terms of the effects parasites have on the immune system, particularly parasite-induced immunodepression, and the effects of cytokines controlling polarization to the Th" or Th# arms of the immune response. In addition, parasites may be affected, directly or indirectly, by cytokines and other immune effector molecules and parasites may themselves produce factors that affect the cells of the immune system. Parasites are, therefore, affected when they themselves, or other organisms, interact with the immune response and, in particular, the cytokine network. The importance of such interactions is discussed in relation to clinical disease and the development and use of vaccines.

Key words: Concomitant infections, cytokines, protozoa, helminths, bacteria, viruses.

field workers and other parasitologists seldom con-  sider more than the single organism that directly The term concomitant infections, alternatively called concerns them. The standard parasitological text mixed infections, traditionally refers to a situation in books are silent on this subject and there is virtually which two or more infectious agents coexist in the nothing about concomitant infections in the more same host. In the light of modern concepts of biology specialized texts on epidemiology (Anderson & May, this definition is insufficiently precise and the 1991; Grenfell & Dobson, 1995; Isham & Medley, definition that will be used here is one in which the 1996), and host behaviour (Barnard & two (or more) concomitant infectious agents are Behnke, 1990; Beckage, 1997), helminth infections specifically designated as being genetically different. and nutrition (Stephenson, 1987), evolution (Brooks This definition permits the inclusion of agents & McLennan, 1993), immunology (Wakelin, 1996) belonging to different species, the commonly ac- or even host-parasite relationships (Toft, cepted view of concomitant infections, and members Aeschlimann & Bolis, 1991). There is some tan- of the same species that are genetically different, for gential reference to hormonal changes induced by example those belonging to a different strain or parasites and possible effects on other parasites by population. In nature, concomitant infections are the Hillgarth & Wingfield (1995) but this is not pursued rule and this has been recognized since the earliest in any depth. There is, therefore, a major gulf recorded times; for example, multiple infections of between the well defined world of text book helminth eggs have been detected in human parasitology, with everything laid out in neat self- coprolites and other human remains from pre- contained sections, and the nicely controlled con- historic sites (see Brothwell & Sandison, 1967; ditions that exist in a laboratory, where there is Cockburn, Cockburn & Reyman, 1998). What is less usually a one to one parasite-host relationship, and well known is that there are numerous interactions, the real world in the field where there may be many both gross and subtle, between different kinds of infections interacting with one another. There are organisms. This fact has been long recognized by many examples of concomitant infections in humans experimental scientists, including parasitologists, and animals (see for example Christensen et al. 1987; who go to great lengths to use animals that are germ Ashford, 1991; Petney & Andrews, 1998; Viera et al. free, specific free (SPF) or harbour a 1998). The infectious agents concerned may be those known fauna or flora (gnotobiotic). Despite the of the same species, related species or distantly widespread acceptance that different organisms related species. Among the best known examples of commonly occurring together in the same hosts can, the interactions between parasites of the same species and do, influence one another directly or indirectly, are the schistosomes where the presence of an ongoing of adult worms inhibits the * Tel: j44 020 7927 2333, Fax: j44 020 7580 9075. establishment of a subsequent infection by larval E-mail: f.cox!lshtm.ac.uk forms, a phenomenon known as concomitant im-

Parasitology (2001), 122, S23–S38. " 2001 Cambridge University Press DOI: 10.1017\S003118200001698X Printed in the United Kingdom F. E. G. Cox S24 munity (Smithers, Terry & Hockley, 1969). This immune response. The key cells are the Th (T phenomenon is also seen in other helminth helper) lymphocytes. At first these cells are un- infections, for example, cestodes (see Heath, 1995). committed but they gradually differentiate into Th" In , an ongoing infection is thought by many and Th# cells, each characterized by the cytokines workers not only to induce, but also to be necessary they produce, until eventually they become fully for to a superimposed infection of differentiated and, when this happens, they are parasites with the same or different genotype, a mutually exclusive. The Th" cells produce T" phenomenon called premunition (Sergent, 1937; cytokines, particularly IL-2 that drives the immune Smith et al. 1999). Well known examples of response towards the production of cytotoxic T (Tc) interactions between more distantly related cells and IFN-γ that drives the immune response organisms are those that exist between the Epstein towards the activation of macrophages. Th# cells, on Barr virus and malaria parasites (Burkitt, 1969) and the other hand, produce IL-4, IL-5, IL-10 and IL- between the Human Immunodeficiency Virus (HIV) 13 that lead to the activation of B cells and the and several parasites of which the best known subsequent production of , and to the examples are Cryptosporidium and Leishmania spp. proliferation and differentiation of . In (see Ambroise-Thomas, this supplement). shorthand, the Th" responses represent the cell- One of the reasons why so little attention has been mediated arm of the immune response and the Th# paid to concomitant infections is that the interactions responses represent the humoral arm. For further involved are complex and difficult to understand. information, there is an excellent account of this Briefly, such interactions can either be ecological, in subject in Klein & Hor) ejs) ı! (1997). Tc cells are ideally which case the rules of ecology, particularly com- suited for the destruction of virus-infected cells, petition for space or resources, apply or immuno- IFN-γ-activated macrophages are involved in the logical where the rules immunology apply. Anderson killing of intracellular and the antibody (1994) has stated, in another context, that ‘the produced by B cells is most effective against interaction between the variables that determine the extracellular pathogens such as helminths. The role typical course of infection in an individual patient of Th" and Th# cells in a number of infectious and those that determine the typical course of diseases is well discussed in the various contributions infection in communities of people is often complex in Romagnani (1996) and, with particular relevance and very non-linear in form’. Everything that is said to helminths, by Pritchard, Hewitt & Moqbel (1997). and implied here is made even more complex in the Parasites are no different from other pathogens in case of mixed infections. A number of ecologists, that they inevitably induce some kind of immune particularly those working with helminths, have response except that Tc cells are less involved in begun to appreciate and take cognizance of mixed parasitic infections than in viral infections (see Cox infections and their implications and a considerable & Wakelin, 1998 and Wakelin, 1996 for general amount of progress has been made in this area accounts of the immune responses to parasites). In (Dobson, 1985, 1990; Poulin, 1998) and some of general, it is widely accepted that protective Th" these aspects will be discussed further in this supple- responses predominate in infections caused by ment by Dobson, Poulin, and Kennedy. However, protozoa whereas Th# responses are more important the more subtle interactions that occur in hosts in immunity to helminth infections. In addition, the co-infected with more than one infectious agent, mutual exclusivity mentioned above frequently particularly those involving immunological re- results in extreme polarization in which one arm sponses, have been less well investigated and this is of the immune response is protective and the the area that will be considered in this article. other counter protective. However, these are generalisations and the details of each individual immune response can differ from time to time or       from stage to stage of an infection (Allen & Maizels, It is a truism that a host harbouring any infectious 1997). agent is not the same as one that is not infected. The polarization of T cells towards cell-mediated Furthermore, hosts harbouring large numbers of or antibody-mediated responses does not depend parasites are not the same as those harbouring small entirely on the infectious agent involved but can be numbers, those harbouring viruses are not the same modulated by pre-existing factors including cyto- as those harbouring bacteria and so on. It is not kines. For example, the presence of IL-12 drives the appropriate here to discuss in detail the nature of all immune response towards the T" pole whereas the the host’s immune responses to infectious agents but presence of IL-4 drives it towards the T# pole (Ma et it is important to appreciate the significance of T al. 1997). Initial or subsequent polarization involves lymphocyte subsets and the cytokine network. the interaction of a number of regulatory cytokines Essentially, from the moment an immunologically some of which act as growth and differentiation intact host is infected with any infectious agent, the factors. What is important here is that these host begins to mount an appropriate protective cytokines, and also effector molecules, act non- Concomitant infections S25

(TLTF) and trypanosome macrophage activating factor (TMAF). TLTF induces lymphocytes to produce IFN-γ which both activates macrophages and promotes trypanosome growth and TMAF also stimulates macrophage activity (see Sternberg, 1998; Hamadien, Bakhiet & Harris, 2000). The production of TLTF is not restricted to T. b. brucei but has also been found in T. b. gambiense, T. b. rhodesiense and T. evansi (Bakhiet et al. 1996a). All the African trypanosomes are, therefore, potentially caught up in a series of interactions in which trypanosome- derived factors activate both T lymphocytes and macrophages. The net effect is that lymphocyte- Fig. 1. Diagrammatic representation showing some of produced IFN-γ enhances trypanosome growth the interactions that exist between African trypanosomes and cytokine network. Trypanosomes produce a number while other trypanosome-derived molecules induce of factors including trypanosome macrophage activating macrophages to produce molecules that inhibit factor (TMAF) and trypanosome-derived lymphocyte lymphocyte activation (Fig. 1). Among other triggering factor (TLTF) that stimulate macrophages parasite-derived molecules there are some of proto- and lymphocytes respectively. IFN-γ, a product of zoan origin that induce the synthesis of IL-12 by stimulated lymphocytes, can act as a trypanosome macrophages (Gazzinelli et al. 1997) and an IFN-γ- growth factor but prostaglandins (PG) and nitric oxide like molecule produced by the nematode Trichuris (NO) produced by macrophages inhibit lymphocyte muris (Grencis & Entwistle, 1997). The precise role activity and hence the production of IFN-γ. of these molecules is unclear but what is important Trypanosomes are therefore enmeshed in a network of here is that these parasite-derived factors can interact cytokines and effector molecules that both stimulate and with the other molecules of the immune system and inhibit their growth and development. In this diagram, positive signals are indicated by open arrows and may be involved in enhancing or depressing the inhibitory ones by stippled arrows. immune response to other organisms and cannot be ignored in any consideration of concomitant infections. specifically. It is therefore possible for any infectious agent to be caught up in the cytokine network. It is now becoming clear that this is what happens in the     case of any agent acquired previously, concurrently or subsequently in the majority of concomitant There have been numerous reports of interactions infections at least under controlled laboratory between parasites and between parasites and other conditions. infectious agents (see Christensen et al. 1987). This is not intended to be a comprehensive review of the subject and many of the examples cited by Christensen et al. will not be reiterated here.     However, this is an attempt to collate and categorize -    some examples of the various interactions that have Although directed at other cells involved in the been recorded and to try to explain them in terms of immune response certain molecules such as trans- what is happening in an infected host. In this forming growth factor-beta (TGF-β) and interferon- respect, the Christensen et al. paper represents the gamma (IFN-γ) can act directly or indirectly on end of an era. 1986 in an important watershed in our parasites. For example, IFN-γ acts as a growth understanding of the interactions that occur between factor for Trypanosoma brucei (Bakhiet et al. 1996b) infectious agents because it was in that year that the and TGF-β is required for the invasion of mam- Th"\Th# dichotomy was suggested, first in mice malian cells by Trypanosoma cruzi (Ming, Ewen & (Mosmann & Coffman, 1989) then in humans Pereira, 1995). Other examples are given by (Romagnani, 1991) and subsequently in all species of Barcinski & Costa-Moreira (1994) and Omer et al. mammals studied. This concept has dominated (2000). thinking about immune responses ever since (see In addition to the molecules of the immune Romagnani, 1996). Prior to this discovery, the system, all parasites produce secreted or excreted various interactions between parasites and other products some of which can themselves affect cells of infectious agents had been difficult to explain and the immune system (see Kaye, 1999). The best mainly centred on attempts to implicate ill-defined studied molecules are those produced by African mechanisms of immunodepression, often referred to trypanosomes, particularly T. brucei brucei; as immunosuppression, brought about by molecules trypanosome-derived lymphocyte triggering factor produced by parasites which facilitate their own F. E. G. Cox S26 survival. The best studied examples of immuno- k21 days it is absolute (Millott & Cox, 1985). In depression are infections with African trypanosomes passing, it must be pointed out that these results are (Greenwood, 1974; Hudson & Terry, 1979), malaria counterintuitive as it might be expected that super- parasites (Greenwood, 1974; Del Giudice, Grau & imposing a piroplasm infection on an ongoing Lambert, 1988) and nematode worms (Behnke, trypanosome infection, during a period of what 1987). According to the theory of immuno- should be trypanosome-induced immunodepression, depression, any concomitant infection that is should result in higher rather than lower piroplasm acquired while the host is experiencing a phase of infections. parasite-induced immunodepression should be able There are, therefore, many different outcomes to establish itself more readily and possibly become resulting from concurrent infections and, from the more virulent or pathogenic. There is, for example, examples cited above, it is clear that these may be a correlation between the occurrence of Burkitt’s unpredictable. In searching for the truth in any lymphoma, caused by infection with the relatively complex situation it is advisable to adopt the advice harmless Epstein-Barr virus, and the presence of of William of Ockham (or Occam) as perpetuated in malaria (Burkitt, 1969). On the other hand, HIV the maxim, Ockham’s razor, which states that in does not seem to have much effect on malaria seeking an explanation, various assumptions need infections or vice versa (Butcher, 1992). not be multiplied needlessly; in other words, if there Not all factors that affect the outcome of con- is a simple explanation there is no need to seek a comitant infections are immunological. Other more complicated one. However, this implies that all factors responsible for a particular outcome include the knowledge necessary to produce a feasible changes in the microenvironment. The induction explanation is available but, unfortunately, it is not. of reticulocytosis in experimental rodent malaria Therefore, the sensible approach is to seek simple infections, for example, should, and does, disad- explanations wherever possible, to look for vantage species such as Plasmodium vinckei and P. exceptions and to modify the original explanation in chabaudi that require mature erythrocytes resulting terms of the exceptions and new knowledge. in lower parasitaemias. However, this explanation In the sections below, selected examples of does not account for the fact that infections with P. interactions between protozoa and viruses, protozoa berghei, which prefers reticulocytes, are similarly and bacteria, protozoa and protozoa, protozoa and affected (see Cox, 1975a, 1978 and below). helminths, helminths and viruses, helminths and These situations described above illustrate some bacteria and between helminths and helminths will of the problems inherent in seeking explanations for be discussed. It must be pointed out, however, that the interactions between the different agents in virtually all the information available comes from concomitant infections because there seem to be as carefully controlled laboratory studies, usually with many exceptions to the ‘rules’ as there are examples. mice, that are sometimes very contrived. However, it It is, therefore, necessary to consider the nature of is likely that these interactions will eventually be the possible outcomes. It is best to start with the shown to apply to natural human and animal diseases simplest examples where a host that is harbouring, and examples of such situations will also be or has harboured, one organism A, is infected with a discussed. different organism, B. There are three outcomes with respect to B: the ensuing infection may be Protozoa and viruses enhanced, suppressed or not affected in any way. However, there is also the reciprocal situation with Viral infections are usually extremely difficult to respect to the infection caused by A, which may also detect and, therefore, the amount of information we be enhanced, depressed or neutral. Thus in this have on interactions between protozoa and viruses is simple situation, there are a number of different limited. Much of what we know comes from possible outcomes. However, this example only takes experiments involving Plasmodium spp. and other into account a subsequent infection acquired at a intraerythrocytic protozoa in mice and rats but there specific point in time during the course of the is no coherent pattern that emerges (see the reviews ongoing infection. The outcome of infection B may by Cox, 1975a, 1978). The intensity of P. berghei well be different if the host harbouring A is infected infections is suppressed in mice infected with West with B at the beginning of the infection, at its peak or Nile virus (Yoeli, Becker & Bernkopf, 1955) or during a chronic phase. For example, the outcome of Newcastle Disease virus (Jahiel et al. 1968b) dual infections with of Babesia microti and T. b. suggesting that virus-induced IFN-α might be brucei in mice varies according to when the piroplasm protective against malaria parasites (Jahiel et al. is administered in relation to the trypanosome 1968a). However, there is no direct evidence that (Millott & Cox, 1985). In this situation, the piro- this is the case but, in this context, it is interesting to plasm infection is always inhibited when the trypano- note that, in humans, infections with P. falciparum some is given beforehand but the inhibition increases are lower in patients co-infected with measles or with the interval between the two infections until at influenza viruses (Rooth & Bjorkman, 1992). Thus Concomitant infections S27 viral infections may ameliorate malarial infections malaria infections in mice and humans (McGregor & but, on the other hand, the non-lethal strains of P. Barr, 1962, see also Houba, 1988) and the en- yoelii and P. chabaudi become lethal in mice infected hancement of viral infections in co-infected animals with the Rowson Parr virus (Cox, Wedderburn & can be explained in these terms. What is not so easy Salaman, 1974) and infections with the Rowson Parr to explain, however, is the finding that the feline or urethane leukaemia virus also enhance Babesia immunodeficiency virus (FIV) causes changes to the microti infections in mice (Cox & Wedderburn, activity of macrophages but this does not affect co- 1972). These results might be due to immuno- infection with Toxoplasma gondii (Lin & Bowman, depression caused by the viruses which, as a group, 1992). Other interactions between T. gondii and tend to be immunosuppressive (Salaman, 1969) but immunosuppressive viruses are reviewed by Lacroix these conflict with those cited above in which et al. (1996). infections in virally infected animals or individuals were actually suppressed. Protozoa and bacteria Turning now to other combinations of protozoa and viruses (other than HIV), there are a number of Most of the information we have about interactions observations that can be attributed to the immuno- between protozoa and bacteria comes from studies depressive effects of the virus infections and on infections with intraerythrocytic protozoa. Early explained in terms of the consequent down regu- studies were mainly concerned with the spirochete, lation of cytokines required for immunity to the Borrelia duttoni which has little effect on infections protozoan. Cryptosporidium parvum infections are with P. berghei (Colas-Belcour & Vervent, 1954) and enhanced in mice experimentally infected with the B. hispanica which causes a slight enhancement of P. murine leukaemia retrovirus LP-BM5 (Darban berghei infections in rats (Sergent & Poncet, 1957). et al. 1991) and this enhancement correlates with As mentioned above, rickettsiae have a dramatic decreased IFN-γ and IL-2 production in the virus- effect on rodent malaria infections and there infected mice (Alak et al. 1993). In naturally infected is a considerable literature on the effects of chickens, infections with C. baileyi are enhanced in Eperythrozoon coccoides and Haemobartonella muris, animals co-infected with the chicken anaemia virus, which both cause anaemia, and the consequent CAV (Hornok et al. 1998). Trypanosoma cruzi reticulocytosis that should favour the development infections are also more severe in mice co-infected of parasites like P. berghei that preferentially invade with viruses; for example, infections with the murine reticulocytes. In fact, the reverse is the case and P. leukaemia virus, MuLV, results in the enhancement berghei infections are suppressed in mice co-infected of T. cruzi infections in mice (Silva et al. 1993) and with E. coccoides (Peters, 1965). Infections with P. this is also the case in mice co-infected with the chabaudi and P. vinckei, that preferentially invade mouse hepatitis virus type 3 (Verinaud et al. 1998). mature erythrocytes, are milder in mice harbouring In the MuLV-infected mice, T cells do not respond E. coccoides which is easier to explain (Cox, 1966). to trypanosome , suggesting immuno- Haemobartonella muris has received less attention but depression on the part of the virus (Silva et al. 1993), rats co-infected with this organism and P. berghei and this is also the proposed explanation of the harbour higher infections of the malaria parasite observations seen in the mouse hepatitis-infected than do uncontaminated controls, which is what one animals (Verinaud et al. 1998). might expect in hosts with an increased proportion There are very few studies on the effects of of the preferred host cells (Hsu & Geiman, 1952; protozoan parasites on infections caused by viruses Smalley, 1975). The interactions between rickettsial but those that have been described all indicate that infections and rodent malaria parasites are important viral infections are enhanced in animals harbouring because of serious problems inherent in interpreting parasitic protozoa. For example, infections with the results obtained in laboratory mice infected with E. murine oncogenic viruses, Murine Sarcoma virus or coccoides (see Cox, 1978). Moloney virus, are more severe in mice co-infected A well explored but essentially experimental with P. yoelii (Salaman, Wedderburn & Bruce- aspect of the possible interactions between bacteria Chwatt, 1969; Wedderburn, 1970, 1974) and mice and protozoa arises from studies in the 1970s that co-infected with T. cruzi and MuLV develop a demonstrated that BGC, Corynebacterium parvum murine form of AIDS which does not occur in and other bacteria and bacterial products protect animals infected with either of these agents alone mice against malaria parasites and piroplasms (see (Silva et al. 1993). The best documented evidence Cox, 1975a). In fact, the number of bacteria and that protozoan infections can enhance viral infections bacterial products that protect mice non-specifically in humans is that relating to the Epstein Barr virus against blood parasites is very large (Cox, 1981) and which normally causes mild or inapparent infections it is very likely that, in the field, bacterial infections but can contribute to the development of Burkitt’s play an important role in modulating infections with lymphoma in individuals exposed to malaria (see De intraerythrocytic protozoa. The most likely expla- The, 1985). Immunodepression is characteristic of nation of the protection is the production of F. E. G. Cox S28 mediators, probably tumor necrosis factor (TNF) between different genera of intraerythrocytic proto- and nitric oxide (NO) by macrophages. This topic is zoa, Plasmodium and Babesia (Cox, H. W. & Milar, discussed more fully elsewhere in this volume by 1968; Cox, F. E. G., 1968). Attempts were initially Clark. made to explain these findings in conventional There are very few reports of interactions between immunological terms, such as the presence of cross- bacteria and protozoa in humans but there are a reacting antigens, but it soon became clear that what number of reports of enhanced bacterial infections, happens is that the superimposed infection becomes particularly in children, suffering from severe ma- involved in non-specific responses involving a num- laria. Increased prevalence and parasite densities of ber of mediators of inflammation, a topic that is P. falciparum appear to correlate with pertussis in discussed in more detail elsewhere in this sup- children in contrast to the suppression of para- plement by Clark. Heterologous immunity is not sitaemias seen in those suffering from viral infections restricted to the parasites of rodents and there is also mentioned above (Rooth & Bjorkman, 1992). It is convincing evidence that there is cross-immunity also well known that bacterial pneumonia is some- between the malaria parasites of non-human prim- times associated with malaria (Bygbjerg & Lanng, ates (Voller, Garnham & Turner, 1966) and some 1982; Mabey, Brown & Greenwood, 1987; Walsh et evidence that infections with P. vivax might reduce al. 2000) and there has been a report of enhanced the severity of P. falciparum infections in humans tuberculosis in a patient with malaria (Hovette et al. (Maitland, Williams & Newbold, 1997). 1999) but the reasons for this are not known. Given In addition to the blood parasites, there are other the importance of malaria it is surprising that the examples of unexpected interactions between related interactions between this disease and bacterial in- protozoa belonging to different species. For example fections has not received much attention even in in mice infected with the coccidians Eimeria epidemiological studies (see Greenwood, 1997). falciformis and E. pragensis, in that order, the cyst output of the latter is enhanced but in the reverse order there is no such effect (Shehu & Nowell, 1998). There are also examples of dramatic interactions Protozoa and other protozoa between distantly related species of protozoa, the There is a massive literature concerned with the most studied being those involving trypanosomes various interactions reported between protozoa and and other blood parasites. Some of the earliest it is only possible here to draw on a few selected investigations were concerned with co-infections examples. These interactions can be divided into two with T. lewisi and P. berghei in rats in which the main groups, interactions between parasites be- parasitaemias due to both infections, particularly the longing to the same species and interactions between trypanosomes, were enhanced (Hughes & Tatum, different species ranging from closely related to 1956; Shmeul, Golensa & Spira, 1975). Experiments distantly related forms. The phenomenon of in mice infected with T. musculi provided similar premunition in malaria infections has already been results in mice co-infected with P. berghei (Bu$ ngener, touched on and will not be discussed further here as 1975), P. yoelii (Cox, 1975b)orBabesia microti (Cox, it is more fully explored by Smith et al. (1999). 1977). Trypanosoma cruzi infections are also en- Mixed infections with different species of malaria hanced in mice infected with P. berghei (Krettli, parasites are common (see Tanner & Baker, 1999) 1977). Although difficult to explain at the time, these and all four species that infect humans have been results can now be explained in terms of immuno- found in a single individual (Purnomo et al. 1999). logically significant molecules, such as IFN-γ, acting Much of what we know about the situation in as trypanosome growth factors as has been discussed humans comes from cross-sectional surveys and above. However, this cannot be the whole story as T. these indicate the involvement of both immuno- b. brucei infections are not enhanced in mice co- logical and density-dependent factors in the regu- infected with B. microti whereas the babesial lation of parasitaemias (Bruce et al. 2000). Such infections are (Millott & Cox, 1985). In rats, studies are at the descriptive stage and it is not infection with T. lewisi enhances Toxoplasma gondii possible to speculate on the mechanisms involved infections (Guerrero, Chinchilla & Abrahams, 1997), without entering into the massive literature con- although the mechanism is not at all clear and could cerned with malaria immunology. The concept of be due to immunodepression or to the effects of specific immunity underlies much of our under- trypanosome-derived molecules. standing of the epidemiology and control of malaria There are a number of reports of reciprocal infections and this assumption appeared to suffer a enhancements of protozoan infections in mice, for major setback when it was demonstrated that there example, P. yoelii and Leishmania mexicana was a certain degree of heterologous immunity (Coleman, Edman & Semprevivo, 1988) and P. yoelii between different species of malaria parasites in and L. amazonensis (Coleman, Edman & rodents (reviewed by Cox, 1978). This was later Semprevivo, 1989). P. berghei infections are extended to the discovery of protective immunity enhanced in rats co-infected with Toxoplasma gondii Concomitant infections S29

(Rifaat et al. 1984) but there is no information about of the worms which, therefore, suffer from the any effects on the toxoplasma infection. There are relationship in a different way (Bell, Adams & also examples of other one-sided interactions. The Ogden, 1984b). Rats infected with T. b. brucei also cyst output in mice infected with the intestinal fail to expel the nematode worm Nippostrongylus flagellates Spironucleus muris and Giardia muris is brasiliensis (Urquhart et al. 1973), as is the case in reduced in animals also infected with B. microti, P. another combination of trypanosome and nematode, berghei or P. yoelii but the blood infections are not T. b. brucei and Trichinella spiralis, in mice where the affected (Brett & Cox, 1982). These authors attribute presence of the trypanosome also has an inhibitory the reduction in cyst output to physiological changes effect on immunity to the worm (Onah & Wakelin, in the gut rather than to any immunological factors 1999). These authors measured IFN-γ and IL-4 and this also seems to apply in the case of mice co- levels, markers for Th" and Th# responses respect- infected with G. muris and Trichinella spiralis ively and found that in the doubly-infected animals (Roberts-Thomson et al. 1976 and see below). levels of IFN-γ were increased and levels of IL-4 Interactions between protozoan infections in humans were reduced and they conclude that in the doubly- are not at all easy to assess but, with the increased use infected animals the immune response is biased to of more sensitive and specific diagnostic methods, it the T" pole thus inhibiting immunity to T. spiralis is likely that in the future there will be a number of which relies on the activation of T# responses. such reports. The findings that trypanosome infections are enhanced in animals co-infected with nematodes relate to laboratory systems but there is some Protozoa and helminths evidence that in domesticated animals the outcome is Intuitively, it would seem unlikely that there could likely to be similar. In a natural situation, N’dama be any interactions between single celled protozoan cattle in The Gambia are more susceptible to and multicellular helminths, particularly as most of infection with T. congolense or T. vivax if they are them occupy different sites in the body and elicit infected with trichostongyle nematodes (Dwinger et very different kinds of immune responses. In fact, in al. 1994) and sheep infected with Haemonchus virtually all situations where protozoa and helminths contortus and T. congolense are able to tolerate either occur together that have been investigated exper- infection but not both (Goossens et al. 1997). imentally, there is some degree of interaction, However, it is impossible to generalise from these sometimes very dramatic (Christensen et al. 1987; findings and those discussed above and conclude that Chieffi, 1992; Petney & Andrews, 1998; see Behnke in dual infections with nematodes and trypanosomes et al. this supplement) Some of these interactions are the trypanosome infection will always be enhanced. now beginning to be subjected to the kind of analysis For example in mice infected with Heligmosomoides involving Th" and Th# cells referred to at the polygyrus and T. musculi the trypanosome infection beginning of this review and this topic is discussed is not enhanced (Bell, Adams & Ogden, 1984a). elsewhere in this supplement with relevance to Schistosome infections interact with a variety of nematode worms in rodents (see paper by Behnke et protozoa, at least in experimental models (see Chieffi, al.). The most studied interactions are those between 1992). Infections with the rodent malaria parasites trypanosomes and the intestinal nematode worm are affected in different ways by the presence of Trichinella spiralis. Mice infected with T. spiralis Schistosoma mansoni. For example, in the vole experience considerably increased Trypanosoma Microtus guentheri, P. berghei infections are enhanced musculi infections when the nematode infection is if the two infections are given within 2 weeks of each initiated 5–10 days before the trypanosome and this other but depressed if the malaria infection is given enhancement is still obvious after 45 days (Bell, seven weeks after the schistosome infection when the Adams & Ogden, 1984a). Similar enhancement of immune response to the worm is most active (Yoeli, the trypanosome infection occurs in strains of mice 1956). There are also reciprocal interactions and P. differing in resistance to T. spiralis suggesting that yoelii actually inhibits the development of schisto- this phenomenon is a general one that overrides the some granulomas in experimentally infected mice inherent susceptibility or resistance to the nematode (Abdel-Wahab et al. 1974). There have been some (Chiejna & Wakelin, 1984). There are also reciprocal attempts to explain the complex and interdependent effects and the expulsion of T. spiralis is inhibited by interactions between schistosomes and malaria infections with T. musculi also indicating a sup- parasites in terms of the Th"\Th# dichotomy. In pressive effect on the host’s immune response, this mice infected with S. mansoni, infections with the time in the other direction (Bell, Adams & Ogden, malaria parasite P. chabaudi are enhanced in animals 1984b). Thus it would seem that, in this model of infected with the worm 8 weeks previously while Th# doubly-infected animals, both the trypanosome and responses to soluble egg antigens are reduced for 4 the nematode benefit although the details of the weeks after the malaria infection (Helmby, Kullberg actual outcome vary from strain to strain of mouse. & Troye-Blomberg, 1998), a finding that also applies However the trypanosome also reduces the fecundity in other situations that will be discussed below. F. E. G. Cox S30

Schistosomes also interact with a number of other T. spiralis and E. vermiformis or E. pragensis differed protozoa and infections with T. cruzi are much more according to the eimerian species; E. vermiformis severe in mice previously infected with S. mansoni delayed the expulsion of the worm whereas E. (Kloetzel, Faleiros & Mendes, 1971) as are infections pragensis did not and the replication of E. vermiformis with Toxoplasma gondii (Kloetzel et al. 1977). was enhanced in the presence of the worm whereas Schistosoma mansoni-infected mice also experience that of E. pragensis was reduced (Rose, Wakelin & more intense infections with the intestinal protozoa Hesketh, 1994). These authors explain the results in Entamoeba muris, Trichomonas muris and Spiro- terms of inflammation and immunological responses. nucleus muris (Higgins-Opitz et al. 1990) but not In rats infected with T. spiralis and E. nieschulzi Leishmania major (Yoshida et al. 1999) although L. there were decreases in the number of adult worms infantum infections are more severe in hamsters and muscle parasitism and also in the numbers of infected with S. mansoni (Mangoud et al. 1998). oocysts produced by the protozoan (Stewart, Turning to the effect of protozoa and schistosome Reddington & Hamilton, 1980). It is possible to infections, L. infantum in hamsters delays S. mansoni interpret these last results in terms of changes to the granuloma formation (Morsy et al. 1998), a finding architecture of the gut as the worms reach the gut similar to that recorded for malaria parasites dis- when it has been severely damaged by the eimerian. cussed above although when mice infected with S. A number of other examples of interactions between mansoni, and undergoing an ongoing Th#-inducing T. spiralis and Eimeria spp. are cited and discussed infection, are infected with Toxoplasma gondii,an by Rose et al. (1994) who conclude that it is not infection that is responsive to Th" cytokines, there possible to predict the outcome of the interactions is a considerable reduction in schistosome granu- between these parasites. Staying with intestinal loma size but there is no evidence of uncontrolled infections and another combination involving T. toxoplasma replication (Marshall et al. 1999). Taken spiralis and the intestinal flagellate, Giardia muris, together, these results suggest that infections with the output of protozoan cysts is decreased in doubly- protozoa that stimulate a Th" response actually infected mice but the worm infection is not affected downregulate Th# responses with the result that the (Roberts-Thomson et al. 1976). The authors at- development of schistosome granulomas, a Th# tribute this decrease in cyst output to changes in the phenomenon, is inhibited. gut rather than to any immunological factors, a There is some indication that schistosomes in- conclusion also reached in the experiments using G. teract with protozoa in the field and, from epidemio- muris and the intraerythrocytic protozoa mentioned logical studies in Egypt, it appears that the above (Brett & Cox, 1982). schistosomes interfere with the acquisition of im- Among other interesting interactions between munity to Entamoeba histolytica and\or E. dispar helminths and protozoa are those between Taenia (Mansour et al. 1997). crassiceps and T. cruzi where, if the two are given to The expulsion of nematode infections is inhibited mice together, there is a slight delay in the onset of in mice infected with blood parasites, for example in the trypanosome parasitaemia whereas if the mice infected with B. microti or B. hylomysci and trypanosome infection is initiated later during the Trichuris muris the expulsion of the worm is delayed, cestode infection there are decreases in the levels of the suggested explanation being the immuno- both IFN-γ and IL-4 and susceptibility to the depression induced by the piroplasms (Phillips & trypanosome infection is markedly enhanced. In Wakelin, 1976) and mice infected with Plasmodium mice infected with T. spiralis and L. infantum 7 berghei suffer from prolonged infections with days later, when IFN-γ levels are already elevated, Nippostrongylus brasiliensis and the self-cure mech- the subsequent leishmania infection is milder and anism is suppressed (Modric! & Mayberry, 1994). the parasite load is reduced (Rousseau et al. 1997) These authors attribute the results to decreased and in mice infected with T. spiralis and T. gondii, production in the doubly-infected mice. also 7 days later, the protozoan infection is also Infections with intraerythrocytic protozoa, there- milder (Afifi et al. 1999). In these experiments fore, have an adverse effect on concomitant nematode infection with T. gondii also protects against the infections. On the other hand, B. microti infections nematode. are not enhanced or prolonged in mice co-infected with Heligmosomoides polygyrus (Behnke, Sinski & Helminths and viruses Wakelin, 1999). Among other records of interactions between Although concurrent infections of helminths and protozoa and helminths is the observation that viruses are common the literature on the subject is infections of Entamoeba histolytica are enhanced in rather limited and it is interesting to note that there mice infected with Syphacla obvelata (Vinayak & are very few reports on the effects of immuno- Chopra, 1978). There have been conflicting results suppressive viruses on the outcome of helminth from studies involving T. spiralis and Eimeria spp. infections (see Markell, John & Krotoski, 1999). The In one study in mice, the outcome of infections with best studied examples are those of the human Concomitant infections S31 lymphotropic virus type 1 (HTVL-1) that enhances hepatica is another helminth that suppresses the infections with Strongyloides stercoralis (see Genta & protective Th" immune response against a bacterial Walzer, 1989). There is little evidence to suggest that infection, in this case Bordetella pertussis (Brady et HIV and schistosomes interact with one another al. 1999). It would appear from these examples that despite the fact that they occur together in many helminth infections that induce protective Th# parts of the world. However, there is some evidence immune responses can also downregulate Th" that human infections with the hepatitis B virus responses and that this might bring about the contribute to liver damage caused by S. mansoni exacerbation of concomitant infections or a failure to (Strauss & Lacet, 1986). There is also evidence that respond to vaccination in infections that are con- the viral infection is actually enhanced by the trolled by Th" responses. presence of the schistosomes and that there is an association between hepatitis B and the severity of Helminths and other helminths schistosomiasis in Brazil (Strauss & Lacet, 1986) and Egypt (Madwar, El Tahawy & Strickland, 1989). There are numerous examples of interactions be- Taken together, these findings indicate that infec- tween helminth worms (see Christensen et al. 1987) tions with helminths can increase the severity of and those involving nematodes of rodents are viral infections. discussed elsewhere in this supplement by Behnke and others. The best studied example of interactions between helminths is the phenomenon of concomi- Helminths and bacteria tant immunity in which the adults of an ongoing Some of the earliest reports of interactions between infection prevent the establishment of another bacteria and helminths are concerned with a infection with larvae of the same species by eliciting phenomenon called ‘prolonged septicemic salmonel- an immune response which the adult worms can losis’ in which patients infected with S. mansoni evade but the new larvae cannot. This seems to be a experienced prolonged bacteraemias due to several common phenomenon in helminth infections and is species of Salmonella. This finding was subsequently best exemplified by schistosomes (Smithers, Terry & extended to other bacteria and the term ‘prolonged Hockley, 1969) and by Echinococcus granulosus (see septicaemic enterobacteriosis’ was coined for this Heath, 1995). These interactions between worms condition (see Chieffi, 1992). It has been suggested belonging to the same species will not be discussed that this phenomenon is due either to immuno- further here. Different species of helminth do, depression induced by the schistosomes or by the however, frequently occur in the same host and can provision of some sort of protection to the bacteria interact with one another. The ecological aspects of (see Chieffi, 1992). There are, however, interactions such concurrent infections are discussed elsewhere in between Escherichia coli toxins and schistosomes in this supplement by Poulin and some of the immuno- mice in which the lethality caused by both agents is logical aspects of interactions between nematode increased (see Chieffi, 1992). Much of the current worms are discussed by Behnke and his colleagues. interest in the effects of bacterial infections on It is only possible to discuss a few examples of helminths is indirect and is concerned with what different kinds of interactions here. In mice con- happens in individuals vaccinated against Myco- currently infected with the nematodes Trichuris bacterium tuberculosis, the causative agent of tu- muris and Heligmosomoides polygyrus the trichurid berculosis, with BCG, particularly the purified infection is rejected more slowly than in animals protein derivative (PPD). BCG stimulates Th" harbouring this parasite alone and the authors immune responses and there is some concern that consider that this is due to a raising of the immune this might bias the response away from protection threshold necessary for the expulsion of the worms which, in the case of the helminths, tends to be Th# (Behnke, Ali & Jenkins, 1984). However, in most dependent. In fact, there is no evidence that this other systems investigated, the superimposed in- happens but there is evidence that the reverse is the fection is suppressed by the presence of the original case and in children sensitized in utero with S. agent. In mice infected with S. mansoni and the haematobium or Wuchereria bancrofti the bias is away cestode Mesocestoides corti, there is a reduction in the from the Th" responses required for protection number of M. corti tetrathyridia and in the intensity against mycobacterial infections (Malhotra et al. of infection in the animals harbouring dual infections 1999). Similarly, there is evidence that infection with (Chernin et al. 1988). In mice infected with S. Onchocerca volvulus may have an inhibitory effect on mansoni and the cestodes Hymenolepis diminuta or the immune responses to M. tuberculosis or M. Rodentolepis microstoma there is an accelerated leprae, the causative agent of leprosy (Stewart et al. expulsion of the cestodes (Andreassen, Odaibo & 1999). These authors also comment on the Christensen, 1990). In mice co-infected with S. significance of these findings with reference to mansoni and T. muris, the Th# response to schisto- reports of increased incidences of lepromatous some eggs appears to be involved in the elimination leprosy in individuals with onchocerciasis. Fasciola of the nematode infection (Curry et al. 1995) and in F. E. G. Cox S32 mice infected with S. mansoni and Strongyloides immunodepression and a superimposed infection is venezuelensis there is a decrease in the numbers of the able to take advantage of this situation. Essentially nematode which the authors attribute to the effects this is no different from the situation in which many of the immune response on the migrating larvae immunocompromised hosts are susceptible to in- (Yoshida et al. 1999). There is also evidence from the tercurrent infections with a range of microorganisms. field that infection with S. mansoni is in some way However, it is too simplistic to assume that any protective against infection with the geohelminths parasitic infection in an immunocompromised host Ascaris lumbricoides, Trichuris trichiura and hook- is likely to be enhanced and, in this context, it is worms (Chamone et al. 1990). Thus, from these few interesting to note that very few parasitic infections examples it is clear that, in most combinations, are actually significantly enhanced in individuals infection with one worm can protect against others infected with HIV (see Ambroise-Thomas, in this but that there are some circumstances in which volume). Some degree of immunodepression is infection with one helminth can enhance infection common, if not universal, during the course of with another. Dual infections may also have syn- infections with parasites and microorganisms but the ergistic effects on the pathology of some infections, methods used to assess the immune status of the host for example children co-infected with hookworms need not necessarily reveal those aspects that are and Trichuris trichiura have significantly less hae- relevant to the superimposed infection. For example, moglobin than children harbouring only one of these many of the early observations on immuno- nematodes (Robertson et al. 1992). depression in parasitic infections were based on counting antibody-producing cells, which is no longer appropriate given our present knowledge of  the roles of T cells in immune responses. Immuno- This review, which of necessity is very selective, is depression during parasitic infections may be due to intended to indicate the range of interactions be- by-products of an ongoing protective immune re- tween infectious agents that might affect the outcome sponse or to factors induced by the parasites of parasitic infections. It should be clear that mixed themselves in order to ensure their own survival or to infections are the rule in natural situations and that damp down immunopathological changes. Various protozoan infections are affected by other protozoa, aspects of these processes are discussed in more helminths, bacteria and viruses while helminth detail in the various contributions in Doenhoff & infections are affected by protozoa, bacteria, viruses Chappell (1997). What is important to understand and other helminths. In virtually every combination here is what the essential elements of a particular that has been examined one or other of the immune response are that render the host more or concomitant agents is affected by the presence of the less susceptible to infection. There may be other other and in many cases both are affected. In addition alternatives to explain the enhanced infections seen to these infectious agents, there are also fungi and during concomitant infections such as factors that prions to consider and virtually nothing is known enhance the growth or development of the parasite about how these interact with parasites. The out- produced as part of the normal immune response or come of any interaction is not necessarily predictable alterations to the cells required for the survival of a and can vary from stage to stage of the infection. The particular parasite. age and sex of the host, factors that have not been considered here, can also influence the outcome of an The Th \Th dichotomy infection. The important thing to be borne in mind " # is that these interactions do occur and cannot be The second important factor in determining the ignored. outcome of an infection is whether or not the established infection is inducing a Th" or a Th# response. The Th immunological milieu involves a Immunodepression " number of molecules and the cells that produce The most common outcomes in dual infections are them, in particular, NK cells, IL-12 and IFN-γ. that the infection caused by one or other of the The initiation of a new immune response in such a agents may be enhanced or depressed, both may be situation is gradually forced towards the Th" pole affected, one may be enhanced and the other and, if the superimposed agent is controlled by Th# depressed or vice versa. In addition, the presence of responses, it is at an advantage in such a situation. one agent can increase or decrease the severity of the The reverse applies if IL-4 predominates in the pathology caused by the other. With all these immunological milieu at the time of the second possibilities the outcomes of any combination might infection. There is now a considerable amount of be unpredictable but there are a number of patterns solid work going on in this area and from the that seem to be consistent and a beginning has been experiments that have been described it looks as if made in unravelling these patterns. The most the pattern described above is of general application. common situation is one in which one agent causes However, it is important to bear in mind that the Concomitant infections S33

Th"\Th# paradigm is not a rigid set of rules (Allen & between the Epstein-Barr virus and malaria (Burkitt, Maizels, 1997) and that there may be switches in the 1969; De The, 1985) where the host appears to lose patterns of Th" and Th# cytokines during the course the T cell control of the virus infection (Whittle et al. of an infection as has been clearly demonstrated in 1984). There are also other examples including the the case of rodent (Taylor-Robinson & increased incidence of lepromatous leprosy in Phillips, 1998). patients with onchocerciasis (Stewart et al. 1999) and more severe strongyloidiasis in patients harbouring Immune effector molecules the virus HTVL-1 (Genta & Walzer, 1989). There is now a vast amount of evidence from experimental A number of molecules involved in the immune studies to suggest that the clinical picture in many response act on a variety of cells and can affect infections may be markedly influenced by the parasites directly. Mention has already been made of presence of unrelated organisms and it is probable IFN-α which, although important in viral infections, that such influences will prove to be the rule rather does not seem to play any significant part in the than the exception. immune responses induced by, or otherwise involved Concomitant infections are also likely to affect the in, parasitic infections. There are, however, a efficacy of vaccines and will influence the design of number of molecules that are relevant, the most new vaccines. It is already known that it is difficult to studied being the lymphocyte product, IFN-γ, and vaccinate children with malaria against tetanus, the macrophage products TNF, TGF-β, NO and typhoid or bacterial meningococcus (Williamson & reactive oxygen intermediates. Regardless of how a Greenwood, 1978, and see Bjo$ rkman, 1988). Chil- particular immune response was initiated these dren sensitized to helminth antigens also appear to molecules act non-specifically and thus a super- have an impaired response to mycobacterial antigens imposed parasite may be affected by effector (Malhotra et al. 1999). New antiparasitic vaccines molecules the production of which it itself has not will have to take account of the possibility of initiated, in other words, the bystander effect. inhibiting the immune responses to antimicrobial and antiviral vaccines by triggering inappropriate Parasite-derived immunomodulatory factors immune responses. Such inappropriate responses It is now clear that a number of parasites produce might also result from chemotherapy which causes molecules that affect cells of the immune response the death of the parasites and the release of directly or indirectly and thus exert immuno- sequestered antigens as occurs in some autoimmune modulatory effects. The best characterized are diseases. It has been suggested that new anti- trypanosome macrophage activating factor (TMAF) parasitic vaccines should be designed to trigger the and trypanosome lymphocyte triggering factor appropriate T" or T# response (Cox, 1997) but care (TLTF) and it is almost certain that a number of will also have to be taken to ensure that the efficacy others will be described. The presence and effects of of such vaccines is not impaired by concomitant such molecules will have to be taken into account infections. when considering concomitant infections. Concomitant infections have long been ignored by parasitologists but the time has now come to accept that such infections may be the rule and not the The significance of studies on concomitant infections exception and to test laboratory findings in the field. It has been the purpose of this review to give some Our understanding of the totality of the immune indication of the range of interactions that occur response, particularly its cytokine control, has now when a host is infected with more than one infectious provided us with tools to analyse what is happening agent. These interactions cover the whole spectrum during the course of mixed infections and it would from the enhancement to suppression of one or other be remiss of us not to take advantage of these tools or both of the co-infecting agents and from the and to apply the findings to the rational control of augmentation to the amelioration of the pathology of parasitic infections in animals and humans. the infection. 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