# The impact of mucociliary clearance on Mycobacterium tuberculosis pathogenesis

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2024 · $200,075

## Abstract

Project Summary/Abstract. Over one million people died from tuberculosis in 2021. Current treatments are
long, costly, and often induce severe adverse effects, but the current vaccine has not been improved in over 100
years. Improved understanding of the host factors that influence Mtb pathogenesis in the lung may dramatically
improve control and transmission of Mtb between individuals. Before entering the alveolar macrophage, Mtb
encounters respiratory mucins. Mucins are glycosylated macromolecules that encompass the first line of defense
against pathogens. Respiratory mucins MUC5B and MUC5AC protect the lung from pathogens via mucociliary
clearance, directly inhibiting antimicrobial growth, and altering macrophage signaling. However, little is known
about how these macromolecules influence Mtb susceptibility and severity. In this pilot grant, we will evaluate
how respiratory mucins impact Mtb pathogenesis using human genetic studies, combined with interrogation of
their mechanism of action via small animal models recapitulating Muc5b or Muc5ac insufficiency, deficiency, or
overexpression. Our long-term goal is to identify strategies for effective Mtb killing within the lung and improve
mucosal delivery of relevant candidate Mtb vaccines. The objective of this grant is to characterize the
mechanisms by which MUC5B and MUC5AC, the two commonest respiratory mucins, influence Mtb
susceptibility and severity in human populations. The rationale for this study is that respiratory mucins are
essential for mucociliary clearance, support a host of extracellular antimicrobial peptides and proteins in the lung,
and coats pathogens to alter their pathogenicity in the lung. Our preliminary data demonstrates that common
genetic variants in the MUC5B promoter region are associated with pulmonary TB and MUC5B mRNA
expression in the lung, while variation in the MUC5AC gene region is associated with TB meningitis mortality
and MUC5AC mRNA expression. The central hypothesis is that MUC5B and MUC5AC are physical barriers to
infection and also modulate macrophage function and systemic immune homeostasis to worsen TB disease
severity. In this grant, we will test this hypothesis by achieving the following specific aims: 1) We will define the
functional SNPs that regulate MUC5B and MUC5AC gene expression in the lung, systemic immune responses
to TB meningitis, and susceptibility to and severity of TB in a Vietnamese cohort. 2) We will determine the
mechanism by which Muc5b and Muc5ac deficiency, knockout, and overexpression influence clinical and
immune responses to Mtb using genetically modified mice infected with Mtb. This contribution is significant
because mucins represent the first line of defense against Mtb infection, but their role in Mtb pathogenesis is
unknown. The proposed work is innovative because we will investigate the mechanisms and effects of a known
TB susceptibility gene using innovative mouse models of disease, combined with the genetic cohorts of T...

## Key facts

- **NIH application ID:** 10813043
- **Project number:** 5R21AI165961-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Javeed Ali Shah
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $200,075
- **Award type:** 5
- **Project period:** 2023-03-21 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10813043

## Citation

> US National Institutes of Health, RePORTER application 10813043, The impact of mucociliary clearance on Mycobacterium tuberculosis pathogenesis (5R21AI165961-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10813043. Licensed CC0.

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