Exploring Host-driven Immunopathological Factors Developing Severe Tuberculosis: Insights from Comparative Mouse Models

TL;DR

This study identifies how immune factors like neutrophil levels and signaling molecules contribute to severe tuberculosis in mice, offering new insights into disease progression.

Contribution

The study reveals novel mechanistic links between neutrophil-to-T cell ratios, granulocyte progenitor expansion, and type I IFN signaling in TB immunopathology.

Findings

C3H/HeJ and A/J mice showed increased TB susceptibility linked to elevated neutrophil infiltration and G-CSF levels.

Depletion of neutrophils or blocking type I IFN reduced disease severity and normalized immune cell ratios.

Strain-specific protective effects were tied to restored neutrophil-to-T cell ratios and reduced GMP expansion.

Abstract

Tuberculosis (TB) pathogenesis arises from complex interactions between host immune responses and the genetic diversity of Mycobacterium tuberculosis (Mtb). To elucidate host determinants of TB immunopathology, we conducted a comparative analysis of inbred mouse strains infected with the highly virulent Mtb K strain. Among the strains tested, C3H/HeJ and A/J mice exhibited markedly increased susceptibility, characterized by elevated pulmonary bacterial burdens and extensive necrotizing lung pathology. Interestingly, at 2 weeks post-infection (PI), both strains showed lower bacterial burdens, limited dissemination, and less pulmonary inflammation than C57BL/6 mice, but at 4 weeks PI, this trend reversed. The increased disease severity was closely associated with pronounced pulmonary neutrophilic infiltration, elevated systemic levels of granulocyte colony-stimulating factor (G-CSF), expansion of Lin⁻Sca-1⁻c-Kit⁺CD34⁺CD16/32⁺ granulocyte-monocyte progenitors (GMPs) in the bone marrow (BM), and a substantially increased pulmonary neutrophil-to-T cell (N/T) ratio, which positively correlated with disease progression. Depletion of neutrophils or blockade of type I IFN from 2 weeks PI significantly ameliorated disease severity, as evidenced by reduced bacterial burden, improved lung pathology, and normalization of the N/T ratio. Notably, IL-10 receptor blockade and aging specifically mitigated disease severity in A/J mice, whereas BCG vaccination conferred greater protection in C3H/HeJ mice. These strain-specific protective effects were consistently associated with restored N/T ratios, normalized GMP levels, and attenuated systemic G-CSF levels. Together, our findings identify the pulmonary N/T ratio and GMP expansion as central, mechanistically linked drivers of type I IFN signaling and neutrophil-mediated TB immunopathology.

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