Research Article: Parasite-microbe-host interactions and cancer risk

Date Published: August 15, 2019

Publisher: Public Library of Science

Author(s): Nolwenn M. Dheilly, Paul W. Ewald, Paul J. Brindley, Raina N. Fichorova, Frédéric Thomas, Laura J. Knoll.


Partial Text

Characterizing the factors that disrupt the cellular barriers to cancer (e.g., cell-cycle arrest, apoptosis, repression of telomerase, cell adhesion, and asymmetric cell division) and are essential to oncogenesis is necessary to identify targets for therapeutic interventions [1]. Exacerbating causes can contribute to cancer by compromising host restraints on cancer rather than breaking barriers; examples of such exacerbating causes are factors that drive angiogenesis, or increased proliferation during pro-inflammatory responses [1]. All viruses that are recognized by the International Agency for Research on Cancer (IARC) as Group 1 carcinogens, namely human papillomaviruses (HPV), Hepatitis B and C viruses (HBV and HCV), Human Herpes Virus type 8 (HHV-8), and Human T-cell lymphotropic virus type 1 (HTLV-1) [2], break barriers to cancer and therefore generate essential causes of their associated cancers [1]. These may be the result of natural selection. For example, from an evolutionary point of view, it is probably advantageous to a virus that its host cell resists cell death, evades the immune system, and proliferates. Other intracellular organisms (bacteria and unicellular eukaryotes) could similarly benefit from altering the cellular mechanisms that prevent oncogenesis. Indeed, the ability of intracellular bacteria and protozoan parasites to block apoptosis is now broadly recognized [3,4]. Increasing evidence implicates bacteria (certain strains of Escherichia coli, Fusobacterium nucleatum, Salmonella Typhi, Chlamydia trachomatis, and a range of Mycoplasma) and protists (Cryptosporidum parvum, Trichomonas vaginalis, Trypanosoma cruzi, Toxoplasma gondii) in cancer development [2, 5–26].

The composition of the microbiome is thought to result from complex co-evolutionary mechanisms among hosts and microbes. Antagonistic pleiotropy refers to genes that are beneficial early in life, and improve fitness, but become detrimental later in life [28]. Recent studies suggest that microbes and microbial communities can have similar effects: microbiome composition induces a life-history trade-off between life span and reproduction in flies [29]. Thus, natural selection will favor establishment of microbes that are either beneficial to the host or present a low cost of infection early in life, even if these microbes promote oncogenesis later in life. Indeed, the human microbiome includes known and often highly prevalent oncogenic microbes, such as Epstein Barr Virus (EBV), that infect 90% of the human population [30], and many members of the gut microbiota are associated with cancer [6]. Only a small fraction of the population carrying oncogenic microbes develops cancer, suggesting that cofactors that exacerbate the susceptibility to cancer are necessary. Other microbes that are not identified as oncogenic may show high prevalence and present as asymptomatic infection, but may enact essential causes of cancer. Microbial communities previously regarded as commensal may have diverse roles in oncogenesis during the long asymptomatic/subclinical period preceding clinical diagnosis of cancer.

Coinfection by multiple parasites is common in the wild. If we consider that any host-associated microbe can move along the parasitism-mutualism spectrum in a context-dependent manner, coinfection is the norm. Viruses, bacteria, archaea, and eukaryotic parasites have coinhabited the same host lineages for hundreds of millions of years and can either directly interact when they inhabit the same host tissue or indirectly interact via modulation of the host immune system. These interactions can influence tumor development and progression.

There are numerous compelling examples of parasites that carry microbes that participate in the infectious process, notably the well-documented Wolbachia-filarial nematodes system [57, 58]. There is even evidence that parasites have received genes from prokaryotic symbionts via horizontal gene transfers, including numerous Wolbachia genes in symbiont-free filarial nematodes [59], the thymidine kinase of C. parvum [60], and the N-acetylneuraminate lyase of T. vaginalis [61], further demonstrating the selective advantage that microbial symbionts confer to their parasitic hosts. Microbial symbionts of parasites can be transmitted to the host and be responsible for inflammatory-associated pathogenesis [62, 63]. In addition, the release of Wolbachia from filarial nematodes and of Trichomonavirus (TVV) from T. vaginalis upon parasite death have significant adverse effects that impair treatment efficiency [62, 63]. Similarly, relapse of Salmonella infection can occur in the absence of antischistosomal treatment, probably because of the antibiotic resistance of Salmonella attached to the blood fluke [64, 65]. Could the ability of parasite-associated microbes to infect host cells, and their role in inflammation, be responsible for oncogenesis, in lieu of their parasitic host?

Interindividual variations in microbial communities associated with the host or with the parasite at the time of infection could explain apparently contradictory results in parasite association with cancer among studies due to variations in microbe prevalence among populations. Variations in microbial communities could also explain why some patients, but not others, develop cancer. The task of identifying the contribution of parasites and microbes to cancer can appear overwhelming, but causal inference is feasible with a combination of experimental and epidemiological studies (Fig 1). Following the systematic characterization of microbes associated with parasites, as proposed by the Parasite Microbiome Project [83], and by leveraging the findings from other projects such as the Human Microbiome project [84, 85], epidemiological and clinical studies of cancer could investigate the potential for coinfection by different parasites and microbes, and investigate their interacting effects. Testing for the role of microbes in cancer attributed to parasites has the potential to propel the field forward by revealing cofactors that contribute to the development of precancerous lesions and to the transition from benign to malignant cancer. The presence of newly identified microbes in archived cancer tissues should also be tested to assess their potential role. The payoff for identifying microbial factors that contribute to oncogenesis would be self-evident and compelling with respect to new leads for clinical intervention and prevention. In particular, if a virus plays a causal role or exacerbates cancer progression, vaccine development would be justified, as demonstrated by the protection against both infection and infection-associated cancers delivered by the acclaimed HBV and HPV vaccines [86, 87].




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