Polymicrobial etiologies of disease: models and perspectives on basic and clinical research.

Polymicrobial diseases involve more than one infectious agent and are particularly common in resource-limited countries where socio-economic conditions support multiple infections with HIV, bacteria, worms, and co-endemic parasites. Polymicrobial diseases impose a serious challenge to global health because the extent of disease burden associated with one agent is masked by influences from other infections that interact with the host and each other in a synergistic and in some cases antagonistic manner, often resulting in many complex pathologies, including cancer. Because these interactions invariably modify host immunity, mono-specific interventions against one agent may fail to provide complete clinical relief and instead promote drug resistance or emergence of secondary outcomes that may be unresponsive to therapy. This problem is vividly illustrated by Plasmodium falciparum malaria, which has persisted as a leading health challenge because of its interactions with HIV, disseminating bacteria, endemic oncogenic viruses (such as EBV and HHV-8), as well as other tropical pathogens. For example, HIV and schistosomiasis can increase malaria transmission and gametocytemia, respectively, whereas filariasis may suppress immunity to the parasite. Also, malaria and HIV can increase the risk for invasive non-typhoidal Salmonella by modifying host inflammatory responses within mucosal barriers, whereas bacterial translocation is believed to facilitate HIV access to lymphoid tissues within gut mucosa where it promotes massive T cell depletion. It has also been shown that underlying bacterial infection in lungs of people suffering from influenza may enhance virus outgrowth by disrupting physical barriers at the target site.
Understanding the molecular and epidemiologic correlates of microbial co-pathogenesis is an important goal that is hampered by the fact that in most cases two or more related or even unrelated phenotypic variants of distinct pathogens (and their encoded genes or microRNAs) may be involved, which limits development of experimental models that can faithfully recreate the natural history of infection in humans. Therefore, new strategies for infectious disease control must be guided by basic and clinical research approaches that consider the multi-layer interactions of co-pathogenic infections. These efforts must integrate hypothesis-driven studies with clinical, epidemiologic, and systems biological models that link the host anti-microbial proteome to the pathogenetic gene registry of co-pathogenic agents. Accordingly, this research topic is launched to stimulate an interdisciplinary presentation of emerging perspectives on paradigms of polymicrobial disease in form of Research Articles, Reviews, or Perspectives on: (a) the immunopathogenic impact of co-infections both within the host and at a population level, (b) molecular nodes of inter- and intra-microbial interactions, (c) methodologies for measurement of co-infection risk, (d) low-cost models that can facilitate elucidation of correlates of bacterial, viral, or parasitic co-pathogenesis, as well as longitudinal analysis and prediction of infection outcomes, (e) translation of multi-component molecular co-infection data to macro-level population studies. It is anticipated that this collective knowledge will inform development of evidence-based tools for surveillance and evaluation of combination (“polydrug”) strategies for management of co-morbid manifestations in the co-infected host.