Viral coinfection promotes tuberculosis immunopathogenesis by type I IFN signaling-dependent impediment of Th1 cell pulmonary influx

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is often exacerbated upon coinfection, but the underlying immunological mechanisms remain unclear. Here, to elucidate these mechanisms, we use an Mtb and lymphocytic choriomeningitis virus coinfection model. Viral coinfection significantly suppresses Mtb-specific IFN-γ production, with elevated bacterial loads and hyperinflammation in the lungs. Type I IFN signaling blockade rescues the Mtb-specific IFN-γ response and ameliorates lung immunopathology. Single-cell sequencing, tissue immunofluorescence staining, and adoptive transfer experiments indicate that viral infection-induced type I IFN signaling could inhibit CXCL9/10 production in myeloid cells, ultimately impairing pulmonary migration of Mtb-specific CD4+ T cells. Thus, our study suggests that augmented and sustained type I IFNs by virus coinfection prior to the pulmonary localization of Mtb-specific Th1 cells exacerbates TB immunopathogenesis by impeding the Mtb-specific Th1 cell influx. Our study highlights a negative function of viral coinfection-induced type I IFN responses in delaying Mtb-specific Th1 responses in the lung.

Early cellular mechanism of type I interferon-driven susceptibility to tuberculosis

“…Sp140 −/− mice are a unique mouse model of the aberrant type I IFN response, as they do not require repeated administration of TLR agonists, viral co-infection, or other perturbations of the innate immune system for type I IFN production (Antonelli et al, 2010; Kang et al, 2022; Mayer-Barber et al, 2014; Moreira-Teixeira et al, 2020; Redford et al, 2014). Other groups have also modeled the type I IFN response by infecting B6 mice with a lineage 2 clinical Mtb strain, like HN878 (Akter et al, 2022; Manca et al, 2001).…”

“…Mice are able to model the viral induced loss of Mtb control seen in humans, with chronic lymphocytic choriomeningitis virus (LCMV), acute LCMV, pneumonia virus of mice, and influenza A virus co-infection with Mtb all exacerbating tuberculosis disease (Kang et al, 2022; Redford et al, 2014; Volkert et al, 1947; Xu et al, 2021). Additionally, virus-induced type I IFN drove the loss of Mtb control during the acute LCMV and influenza co-infections (Kang et al, 2022; Redford et al, 2014).…”

“…Mice are able to model the viral induced loss of Mtb control seen in humans, with chronic lymphocytic choriomeningitis virus (LCMV), acute LCMV, pneumonia virus of mice, and influenza A virus co-infection with Mtb all exacerbating tuberculosis disease (Kang et al, 2022; Redford et al, 2014; Volkert et al, 1947; Xu et al, 2021). Additionally, virus-induced type I IFN drove the loss of Mtb control during the acute LCMV and influenza co-infections (Kang et al, 2022; Redford et al, 2014). However, co-infection studies make it challenging to understand the cellular mechanism behind Mtb susceptibility, as perturbations such as type I IFN receptor blockade simultaneously impact viral and bacterial control.…”

Neutrophils reprograms the bone marrow to impair T-cell immunity during tuberculosis

“…Lineage 2 strains such as Mtb HN878 induces higher concentration of IFNa/b than the commonly used laboratory strains, and the virulence mechanism is linked to IFN-I-mediated impairment of Th1 immune response 39 . IFN-I has been shown to inhibit T-cell proliferation in vitro 66 and delays Th1 response in the lung in a mouse model of LCMV-Mtb coinfection 67 . Here we showed that IFN-I inhibition in Mtb infected susceptible mice curtails neutrophil influx, augments T-cell proliferation, and most importantly improved the disease outcome.…”

Protective Efficacy and Immunogenicity of Rv0351/Rv3628 Subunit Vaccine Formulated in Different Adjuvants Against Mycobacterium tuberculosis Infection

“…To perfuse the lungs, cold PBS containing heparin was injected into the heart until the lungs appeared white. Then, single-cell suspension of the lung and spleen was prepared as previously described ( 23 ). For phenotypic analysis of lymphocytes, single-cell suspensions were stained with the following Abs; BD Biosciences (San Jose, CA, USA): anti-CD4 (RM4-5)-PerCP-Cy5.5, anti-CD8a(53-6.7)-FITC; eBioscience (San Diego, CA, USA): anti-CD8a(53-6.7)-PerCPCy5.5; Biolegend (San Diego, CA, USA): anti-CD4(RM4-5)-BV605.…”