# 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.

## Key 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.