Viral infectious diseases severity: co-presence of transcriptionally active microbes (TAMs) can play an integral role for disease severity

Abstract

Humans have been challenged by infectious diseases for all of their recorded history, and are continually being affected even today. Next-generation sequencing (NGS) has enabled identification of, i) culture independent microbes, ii) emerging disease-causing pathogens, and iii) understanding of the genome architecture. This, in turn, has highlighted that pathogen/s are not a monolith, and thereby allowing for the differentiation of the wide-ranging disease symptoms, albeit infected by a primary pathogen. The conventional 'one disease - one pathogen' paradigm has been positively revisited by considering limited yet important evidence of the co-presence of multiple transcriptionally active microbes (TAMs), potential pathogens, in various infectious diseases, including the COVID-19 pandemic. The ubiquitous microbiota presence inside humans gives reason to hypothesize that the microbiome, especially TAMs, contributes to disease etiology. Herein, we discuss current evidence and inferences on the co-infecting microbes particularly in the diseases caused by the RNA viruses - Influenza, Dengue, and the SARS-CoV-2. We have highlighted that the specific alterations in the microbial taxonomic abundances (dysbiosis) is functionally connected to the exposure of primary infecting pathogen/s. The microbial presence is intertwined with the differential host immune response modulating differential disease trajectories. The microbiota-host interactions have been shown to modulate the host immune responses to Influenza and SARS-CoV-2 infection, wherein the active commensal microbes are involved in the generation of virus-specific CD4 and CD8 T-cells following the influenza virus infection. Furthermore, COVID-19 dysbiosis causes an increase in inflammatory cytokines such as IL-6, TNF-α, and IL-1β, which might be one of the important predisposing factors for severe infection. Through this article, we aim to provide a comprehensive view of functional microbiomes that can have a significant regulatory impact on predicting disease severity (mild, moderate and severe), as well as clinical outcome (survival and mortality). This can offer fresh perspectives on the novel microbial biomarkers for stratifying patients for severe disease symptoms, disease prevention and augmenting treatment regimens.

Keywords: RNA viruses; disease severity; immune response; infectious diseases; microbial biomarkers; microbiome; transcriptionally active microbes (TAMs).

Figure 1

Disease severity sub-phenotypes, clinical outcome, and modulators. The complex yet intricately regulated interplay of variables governs disease severity sub-phenotypes and differential clinical outcome. Understanding pathogen and host responses integrally, along with the role of microbes, influence the trajectories of disease progression and clinical outcome.

Figure 2

Potential mechanisms of influenza virus infection and bacterial co-infections. The influenza virus produces IFN III, which stimulates STAT1, which then activates SOCS1 to regulate antimicrobial peptides, resulting in enhanced co-infection. The binding of influenza virus to sialic acid receptors causes lung epithelial damage, increasing membrane permeability to bacterial infections. Desensitization of alveolar macrophages to TLR ligands prevents the immune system from recruiting appropriate neutrophils, resulting in increased bacterial burden. The influenza virus’s non-structural PB1-F2 protein increases inflammatory responses to co-pathogens by inducing apoptosis in immunological and lung epithelial cells.

Figure 3

Microbial signatures associated with COVID-19 disease severity. SARS-CoV-2 infection causes gut and respiratory microbial dysbiosis, which results in several disease sub-phenotypes, mild, moderate, severe, and mortality, each with its own set of microbial signatures that can be identified as biomarkers for the specific phenotype.

Figure 4

Co-infection of dengue with viruses, bacteria, and fungi increases the dengue viral titre, and even increases the symptoms and mortality of the disease. The figure depicts the known pathogens co-infecting along with the dengue virus and their association with disease severity.

Figure 5

Information to Knowledge. Understanding the known, overcoming the challenges, transforming them into opportunities, and reaping the benefits of this knowledge - in public health and clinical decision making - will augment future pandemic preparedness.