Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Malaria Pathogenesis Danny A. Milner, Jr. Harvard T.H.Chan School of Public Health, American Society for Clinical Pathology, Center for Global Health, Chicago, Illinois 60603 Correspondence: [email protected] In the mosquito–human life cycle, the six species of malaria parasites infecting humans (Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale wallickeri, Plasmodium ovale curtisi, Plasmodium malariae, and Plasmodium knowlesi) undergo 10 or more mor- phologicalstates, replicate fromsingle to 10,000þ cells, andvary in total populationfrom one to many more than 106 organisms. In the human host, only a small number of these morpho- logical stages lead to clinical disease and the vast majority of all malaria-infected patients in the world produce few (if any) symptoms in the human. Human clinical disease (e.g., fever, anemia, coma) is the result of the parasite preprogrammed biology in concert with the human pathophysiological response. Caveats and corollaries that add variation to this host–parasite interaction include parasite genetic diversity of key proteins, coinfections, comorbidities, delays in treatment, human polymorphisms, and environmental determinants. athogenesis, the manner of development of a et al. 2003a,b; Llinas and DeRisi 2004). In the Pdisease, for a human malaria clinical illness mosquito–human life cycle, however, this par- is a complex story that has many players, set- asite, along with the other five species infecting tings, and potential outcomes. As with any truly humans (Plasmodium vivax, Plasmodium ovale successful parasite, the observed outcome of wallickeri, Plasmodium ovale curtisi, Plasmodi- evolution in malaria is the undisturbed transi- um malariae, and Plasmodium knowlesi), un- tion from mosquito to human to mosquito with dergoes 10 or more morphological states, repli- little impact on the vector and host. Although cate from a single to 10,000þ cells, and vary in impact of malaria can be seen at the individual, total population from one to many more than www.perspectivesinmedicine.org community, country, and global level, from the 106 organisms (Liu et al. 2011; Cator et al. 2012; parasite’s perspective, a healthy host serving as Dixon et al. 2012; Mohandas and An 2012; two blood meals with a bit of fever in between is Antinori et al. 2013; Wright and Rayner 2014; the norm. In fact, human clinical disease is quite Cui et al. 2015; Josling and Llinas 2015; Stone rare relative to the global interaction network of et al. 2015). In addition, all of these parasites mosquitoes and humans. (with the exception of P. knowlesi in humans) The biology of Plasmodium falciparum ma- have been exposed for thousands of millennia to laria parasites, as measured in vitro, is finite, the physical, immunological, and more recently predictable, and easily experimentally per- chemotherapeutic barriers in mosquitoes and turbed during the 48-hour life cycle (Bozdech humans, which places tremendous selection Editors: Dyann F. Wirth and Pedro L. Alonso Additional Perspectives on Malaria: Biology in the Era of Eradication available at www.perspectivesinmedicine.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a025569 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press D.A. Milner pressure across the species (Sabeti et al. 2002; iological response. Caveats and corollaries that Volkman et al. 2007; Ban˜uls et al. 2013; Perry add variation to this host–parasite interac- 2014). It is clearly a finely tuned, well-rehearsed, tion include parasite genetic diversity of key and deftly executed program. proteins, coinfections, comorbidities, delays A similar selection pressure has been placed in treatment, human polymorphisms, and en- on humans and resulted in such fascinating evo- vironmental determinants (Goncalves et al. lutionary outcomes as sickle cell disease, hemo- 2014). The final clinical disease result includes globinopathies, cytokine mutations, and en- a spectrum of fever, anemia, and coma, among zyme deficiency, which confer, as a conceptual many others (Hafalla et al. 2011; Oakley et al. group, the ability to survive to maturity and 2011; Grau and Craig 2012). reproduction (Ban˜uls et al. 2013; Perry 2014). When one questions, “how do we get rid of Death from malaria at an age less than 6 years cerebral malaria?” (one of the more common (the current most common demographic) can- causes of death), it is surprising to no one to not be a goal of the parasite (speaking teleolog- hear the answer, “reduce the overall burden of ically) and, thus, its occurrence should be cause malaria disease.” This may seem simple but, in for concern and investigation. However, the rar- fact, is a complex answer. Interventions with ity of this event (438,000 out of 214,000,000 rapid drug treatment for anyone with a fever clinical cases or 0.2%) leaves the unfortunate will drastically reduce the burden of mortality mortality as an aberrant footnote in the overall (sometimes to zero) in a given location (Clark biology of the species as a whole (WHO 2015). et al. 2010). The treatment probably not only We should not, however, accept even one death staves off a prolonged acute disease state (which from a preventable and treatable disease. may be a component of cerebral malaria [CM]) When we turn to the parasite inside the but also provides an antigen source to the im- human host, only a small number of these mor- mune system to create antibody and other re- phological stages lead to clinical disease and sponses that may quiet future infections. This the vast majority of all malaria-infected patients effect, however, only lasts as long as the diversity in the world produce few (if any) symptoms in of the parasite is stable (a result of endemicity) the human (WHO 2015). This is a crucial point and the drug access continues (a result of infra- of the biology that is often missed or ignored structure stability). In aworld where eradication by experimentalists and “single-mechanism” is a goal for malaria, the incidence of CM with focused scientists. Every person who is infected multiple interventions may decrease or even with malaria (regardless of whether or not they vanish in the current at-risk population (chil- show symptoms) has the parasite go through dren less than 6 years of age in sub-Saharan www.perspectivesinmedicine.org the exact same life-cycle morphological changes Africa). However, the risk of CM may simply andhuman–parasiteinteractions.Disease,thus, shift to these same children at a later stage (or must be the result of exaggeration of this baseline their children) as a region moves from high en- interaction, which, as mentioned, is beneficial to demicity to low endemicity. During this entire neither the parasite nor the human. Further ev- process, however, the biology of the parasite will idence for this lies, obviously, within the overall remain relatively stable and, thus, the risk for rarity of such events. Moreover, there are rela- any of the currently observed diseases states tively few physiological states the parasite can will still exist. How, where, and why these dis- achieve inside the human host—all of this biol- ease states emerge (or vanish) is a product of ogy is accomplished with a meager 6000 genes, many factors beyond the parasite, the vast ma- most of which have no known function (Boz- jority of which are within our control. dech et al. 2003a,b; Daily et al. 2007; Milner et al. 2012). UNCOMPLICATED MALARIA Human clinical disease is, thus, the result of the interaction of the parasite preprogrammed Within the geographic regions where the hu- biology in concert with the human pathophys- man population is at risk for malaria infection 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a025569 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Malaria Pathogenesis (2.5 billion), annually 215,000,000 clinical in- others (Clark et al. 2008; McCall and Sauerwein fections occur for which patients have symp- 2010; Freitas do Rosario and Langhorne 2012; toms and seek medical attention. Patient illness Gun et al. 2014; Hunt et al. 2014). In subsequent represents, however, a subset of all individuals infections, some degree of antibody production who have been bitten by infected mosquitoes produced by the prior macrophage–T-cell–B- and a much larger portion of the “at-risk” pop- cell axis of the immune system confers addi- ulation would show a positive malaria smear or tional macrophage activity leading to a more other diagnostic test if they were screened efficient clearance of parasites and production (asymptomatic infection, true number variable of new antibodies (Wykes and Good 2006; Frei- and difficult to estimate) (malERAConsultative tas do Rosario and Langhorne 2012; Krzych Group on Diagnoses and Diagnostics 2011; et al. 2014; Hviid et al. 2015). As the human McMorrow et al. 2011; Laishram et al. 2012; Ba- host immune system works its way through biker et al. 2013; Lin et al. 2014; Stone et al. the continuously presented parasite protein 2015). The exact malaria parasite biology within repertoire, additional antibodies develop con- these two groups is probably very similar with ferring additional protection. the essential differences being due to the human Uncomplicated malaria is easily treated immune response, number of prior infections, during each symptomatic episode with antima- and exposure profile (Doolan and Martinez- larias specific to the parasite and the vast ma- Alier 2006; Dzikowski et al. 2006; Marsh and jority of patients easily clear the infection when Kinyanjui 2006; De Leenheer and Pilyugin treated with proper compliance.