Co-infections as Modulators of Disease Outcome: Minor Players or Major Players?

Abstract

Human host and pathogen interaction is dynamic in nature and often modulated by co-pathogens with a functional role in delineating the physiological outcome of infection. Co-infection may present either as a pre-existing pathogen which is accentuated by the introduction of a new pathogen or may appear in the form of new infection acquired secondarily due to a compromised immune system. Using diverse examples of co-infecting pathogens such as Human Immunodeficiency Virus, Mycobacterium tuberculosis and Hepatitis C Virus, we have highlighted the role of co-infections in modulating disease severity and clinical outcome. This interaction happens at multiple hierarchies, which are inclusive of stress and immunological responses and together modulate the disease severity. Already published literature provides much evidence in favor of the occurrence of co-infections during SARS-CoV-2 infection, which eventually impacts the Coronavirus disease-19 outcome. The availability of biological models like 3D organoids, mice, cell lines and mathematical models provide us with an opportunity to understand the role and mechanism of specific co-infections. Exploration of multi-omics-based interactions across co-infecting pathogens may provide deeper insights into their role in disease modulation.

Keywords: HCV; HIV; MTB; co-infection; disease severity; immune response; oxidative stress.

FIGURE 1

Co-infection modulating oxidative stress, immune response, and disease severity. The primary infection leads to an increase in oxidative stress, which is further enhanced by the secondary infection and eventually leads to dysregulation of the immune response. Taken together, this leads to tissue damage and acute disease outcomes.

FIGURE 2

Role of co-infections in regulating oxidative stress. Co-infection of Hepatitis C Virus (HIV) with Mycobacterium tuberculosis (MTb) and human immunodeficiency virus (HCV) primes to a disproportion of oxidative stress and antioxidant markers leading to various disease outcomes such as liver fibrosis and inflammation. There are multiple Oxidative stress markers as highlighted above.

FIGURE 3

Co-infection in regulating the immune response. Various chemokines and immune cells show dysregulation during co-infection state which enhances disease severity such as liver fibrosis, hepatocyte inflammation, increase in MTb pathology, Granuloma disruption, and the progression of HIV to Acquired Immunodeficiency Syndrome (AIDS).

FIGURE 4

Different models to study co-infection. Various model systems (mice models, cell lines, organoids, and mathematical models) can be potentially harnessed to decipher the role of co-infections. The figure also shows the advantages and disadvantages associated with various model systems mentioned.

FIGURE 5

Hierarchical role of co-infections as cause, modulator and effector of clinical outcomes. The figure highlights the importance of an integrative approach across multiple hierarchies to study co-infections, from the perspective of, (A) interacting microorganisms (Red), (B) nature of interactions between them (Yellow), (C) mechanisms mediating interactions (Magenta), (D) macro level effects of co-infections (Green), (E) Public health interventions affected by co-infections (Green circles), and (F) multi-omics approaches to study of co-infections (Outer boxes).