M.tb diminishes SARS-CoV-2 severity through innate immune priming

Abstract

Early in the coronavirus disease 2019 (COVID-19) pandemic, individuals with chronic lung conditions, including tuberculosis (TB), were recognized to be at elevated risk for severe COVID-19 outcomes. Despite this concern, clinical studies have reported inconclusive evidence regarding the specific risks SARS-CoV-2 poses to the over 10 million individuals infected with Mycobacterium tuberculosis (M.tb). M.tb infection is well-characterized by a persistent, robust proinflammatory immune response within the lung parenchyma, predominantly driven by IFNγ and T helper 1 (Th1) responses. IFNγ is known for its antiviral properties and its ability to activate a range of interferon-stimulated genes (ISGs) in various cell subsets, including epithelial cells. Therefore, we hypothesized that primary infection with M.tb would induce an immune response, characterized by elevated IFNγ levels, that promotes the transcription of ISGs, creating an antiviral environment that primes the lung to better restrict viral replication upon secondary infection with SARS-CoV-2. Our study aims to dissect the complex interactions between M.tb and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a co-infection model, focusing on how the innate immune response induced by M.tb can modulate viral replication. To investigate this, we developed an M.tb and SARS-CoV-2 co-infection model utilizing transgenic K18-hACE2 mice. Mice were first infected with a low-dose aerosol of M.tb HN878, followed by intranasal infection with a sublethal dose of SARS-CoV-2 variant Beta. We then conducted an in-depth characterization of the co-infection model and employed mechanistic in vitro assays to evaluate the dynamics of the immune response. Our investigation centered on the role of cytokine-mediated signaling in lung epithelial cells, particularly how these signals trigger the upregulation of antiviral genes that serve as a preemptive defense against SARS-CoV-2. Our findings reveal that IFNγ induced by M.tb infection is pivotal in activating antiviral pathways within lung epithelial cells, thereby limiting viral replication and reducing the overall severity of SARS-CoV-2 infection. We have identified key immune responses that play a critical role in this protective response, highlighting potential therapeutic targets that could be exploited to enhance antiviral immunity in the context of co-infection. In all, this study provides an analysis of the immune pathways activated by a pre-existing bacterial M.tb infection that confer protection against SARS-CoV-2. By identifying the molecular players involved, our research offers novel insights into potential therapeutic strategies of IFNγ that could be harnessed to mitigate the impact of COVID-19, particularly in populations with high TB burden.