Kotob et al. Vet Res (2016) 47:98 DOI 10.1186/s13567-016-0383-4 REVIEW Open Access The impact of co‑infections on fish: a review Mohamed H. Kotob1,2, Simon Menanteau‑Ledouble1, Gokhlesh Kumar1, Mahmoud Abdelzaher2 and Mansour El‑Matbouli1* Abstract Co-infections are very common in nature and occur when hosts are infected by two or more different pathogens either by simultaneous or secondary infections so that two or more infectious agents are active together in the same host. Co-infections have a fundamental effect and can alter the course and the severity of different fish diseases. How‑ ever, co-infection effect has still received limited scrutiny in aquatic animals like fish and available data on this subject is still scarce. The susceptibility of fish to different pathogens could be changed during mixed infections causing the appearance of sudden fish outbreaks. In this review, we focus on the synergistic and antagonistic interactions occur‑ ring during co-infections by homologous or heterologous pathogens. We present a concise summary about the pre‑ sent knowledge regarding co-infections in fish. More research is needed to better understand the immune response of fish during mixed infections as these could have an important impact on the development of new strategies for disease control programs and vaccination in fish. Table of contents 1 Introduction 1 Introduction The subject of co-infections of aquatic animals by differ- 2 Co‑infections with homologous pathogens ent pathogens has received little attention even though such infections are common in nature. Co-infections are 2.1 Bacterial co‑infections defined by infection of the host by two or more geneti- 2.2 Viral co‑infections cally different pathogens where each pathogen has patho- 2.3 Parasitic co‑infections genic effects and causes harm to the host in coincidence 3 Co‑infections with heterologous pathogens with other pathogens [1, 2]. Several other terms are used 3.1 Parasitic and bacterial co‑infections sometime to describe co-infections and include pol- ymicrobial diseases, complicated infections, concurrent 3.2 Parasitic and viral co‑infections infections, mixed infections, multiple infections, dual 3.3 Bacterial and viral co‑infections infections, secondary infections and super infections [2]. 3.4 Fungal and bacterial co‑infections Many researchers have concentrated only on single infec- 4 Conclusions tions, classifying the other agent as opportunistic and mostly ignoring it so in this review article we will focus on distinguishing the infections caused by more than one organism. During episodes of co-infection, interactions between the infectious agents yield to varied outcomes: the load of one or both pathogens may be increased, one or both may be suppressed or one may be increased *Correspondence: Mansour.El‑[email protected] and the other suppressed [1]. The natural environments 1 Clinical Division of Fish Medicine, Department for Farm Animals in which animals live are varied and harbor a variety of and Veterinary Public Health, University of Veterinary Medicine, Vienna, Austria heterogeneous micro-organisms including parasitic and Full list of author information is available at the end of the article non-parasitic species and co-infection are a frequent © 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kotob et al. Vet Res (2016) 47:98 Page 2 of 12 occurrence. There is therefore, a considerable necessity to how frequent co-infections can be and because of the investigate the interactions occurring between these spe- potentially important impact that co-infections can have cies during mixed infections and the deleterious effects of on the development of a disease, it is important to under- multi-infections on fish disease pathogenesis, prognosis, stand how defensive immunity to a specific pathogen can and treatment [3–5]. occur in the host infected with multiple pathogens. Stud- During co-infections, pathogens can compete with ying different co-infection models is central to the devel- each other for resources or target sites inside the same opment of new effective vaccination and disease control host. Alternatively, sometimes one pathogen can alter strategies [6]. In the present article, we review recent the immune response of the host against the subsequent studies on co-infections of fish by homologous and het- infections by other pathogens either by suppressing or erologous pathogens. The impact of these co-infections priming the immune system [6, 7]. This can result in a on the susceptibility of the fish, the course and sever- change of the host susceptibility to infection and affect ity of the infection and the interactions between differ- the host-pathogen dynamics, infection biology, dis- ent pathogens are also reviewed in different co-infection ease severity, duration of infection and host pathology models. Tables 1 and 2 summarize the different interac- [7, 8]. Therefore, the interactions between co-occurring tions occurring between different homologous and heter- pathogens can be either synergistic or antagonistic [1, ologous pathogens in fish during co-infections. 9]. Synergistic effects can occur when the first pathogen induces immunosuppression in the host and hinders the 2 Co‑infections with homologous pathogens immune response against subsequent infections, lead- 2.1 Bacterial co‑infections ing to an increase in the severity of the infections and The subject of bacterial co-infections in fish is one that mortality rates [7, 9]. Antagonistic effects, however, can has yet to receive the scrutiny it deserves and includes result from competition of direct pathogens for nutrients dual, triple or multiple bacterial infections. It has been and places and limit the population size of the infectious reported that artificial infection of channel catfish, Icta- agents and, in some cases, alter the site of infection [10]. lurus punctatus by the enterobacterium Edwardsiella In other cases, the antagonistic effects happen when the ictaluri elicits a bacteraemia with motile aeromonad first pathogen triggers and modulates the host immune species, Aeromonas hydrophila [16]. This was confirmed response and hinders the second pathogen [11]. later by Crumlish et al. [17] who repeated these results In humans, several publications have described the with Vietnamese catfish, Pangasianodon hypophthal- effect of one pathogen on the abundance of other path- mus. These authors, however, showed that the reverse is ogens co-infecting the same host and the intensity of not true and that artificial infection with A. hydrophila infection estimated through measures of viral load, para- does not result in shedding of E. ictaluri [17]. Moreo- sitic egg counts, antibody reaction and immune response, ver, artificial co-infection challenge of Vietnamese cat- bacterial burdens in tissues and/or the host survival fish with both bacteria using an immersion route caused rate and recovery time [4]. Immunosuppressed people higher cumulative mortalities (95%) in the co-infected infected with human immunodeficiency virus (HIV- group and (80%) in E. ictaluri only infected fish when 1) have shown an increased susceptibility to secondary compared to the very low mortalities (10%) in the fish infections such as tuberculosis, which promotes HIV-1 exposed to A. hydrophila alone [17]. Based on these replication and increases the viral load [12]. Similarly, results, the authors suggest that while E. ictaluri acts like the susceptibility of HIV-1 infected persons to secondary a primary pathogen, the role of A. hydrophila is more infection with malaria has been shown to be increased opportunistic [17]. six times [13]. Naturally, concurrent infection of E. ictaluri and Fla- Chronic helminth infections, particularly in humans, vobacterium columnare in striped catfish, Pangasianodon produce a strong T helper 2 (Th2) and regulatory hypophthalmus in Thailand has also been reported [18]. immune response. This influences the immune response Dong et al. [18] experimentally challenged the striped to other unrelated pathogens during mixed infections, for catfish juveniles with single and both bacteria using the example reducing the inflammatory response, as well as immersion (i.m) and injection (i.p) routes and the results the efficacy of disease vaccines [14, 15]. showed high cumulative mortality in co-infected fish in In the aquatic environment, fish are commonly exposed both i.m. and i.p. routes when compared to single infec- to heterogeneous infectious macro or micro-organisms. tion of E. ictaluri or F. columnare and the co-infected fish However, little is known about how the presence of one showed the clinical signs of both diseases. The results pathogen can affect the load of other pathogens and how obtained by Crumlish et al. [17] and Dong et al. [18] the host mortality rate will be changed during co-infec- mimicked the natural outbreaks of the disease in striped tion in comparison with single infection [9]. Because of catfish farms in Vietnam and