Evaluation of Myeloperoxidase as Target for Host-Directed Therapy in Tuberculosis In Vivo.

Lara C Linnemann,Ulrich E Schaible,Tobias K Dallenga

doi:10.3390/ijms23052554

Abstract

Due to the rise of tuberculosis cases infected with multi and extensively drug-resistant Mycobacterium tuberculosis strains and the emergence of isolates resistant to antibiotics newly in clinical use, host-directed therapies targeting pathogenesis-associated immune pathways adjunct to antibiotics may ameliorate disease and bacterial clearance. Active tuberculosis is characterized by neutrophil-mediated lung pathology and tissue destruction. Previously, we showed that preventing M. tuberculosis induced necrosis in human neutrophils by inhibition of myeloperoxidase (MPO) promoted default apoptosis and subsequent control of mycobacteria by macrophages taking up the mycobacteria-infected neutrophils. To translate our findings in an in vivo model, we tested the MPO inhibitor 4-aminobenzoic acid hydrazide (ABAH) in C3HeB/FeJ mice, which are highly susceptible to M. tuberculosis infection manifesting in neutrophil-associated necrotic granulomas. MPO inhibition alone or as co-treatment with isoniazid, a first-line antibiotic in tuberculosis treatment, did not result in reduced bacterial burden, improved pathology, or altered infiltrating immune cell compositions. MPO inhibition failed to prevent M. tuberculosis induced neutrophil necrosis in C3Heb/FeJ mice in vivo as well as in murine neutrophils in vitro. In contrast to human neutrophils, murine neutrophils do not respond to M. tuberculosis infection in an MPO-dependent manner. Thus, the murine C3HeB/FeJ model does not fully resemble the pathomechanisms in active human tuberculosis. Consequently, murine infection models of tuberculosis are not necessarily adequate to evaluate host-directed therapies targeting neutrophils in vivo.

Highlights

IntroductionIn certain East European and Asian countries, such as Moldova, Belarus, Russia, and Turkmenistan, among others, ≥20% of all new tuberculosis cases are drug-resistant
Accepted: 23 February 2022With nearly half a million patients falling ill with drug-resistant tuberculosis annually and treatment success rates below 50%, multi and extensively drug-resistant strains of the Mycobacterium tuberculosis complex remain a threat to public health systems worldwide [1].In certain East European and Asian countries, such as Moldova, Belarus, Russia, and Turkmenistan, among others, ≥20% of all new tuberculosis cases are drug-resistant
Limits M. tuberculosis induced and MPO-mediated necrotic cell death in vitro and promotes control of mycobacterial growth, we hypothesized that aminobenzoic acid hydrazide (ABAH) treatment can be beneficial in vivo against experimental tuberculosis in susceptible C3HeB/FeJ mice where neutrophils are involved in disease exacerbation

Summary

Introduction

In certain East European and Asian countries, such as Moldova, Belarus, Russia, and Turkmenistan, among others, ≥20% of all new tuberculosis cases are drug-resistant In those countries, ≥50% of all patients with drug-resistant tuberculosis have previously been treated for tuberculosis, suggesting preceding insufficient treatment or failure. M. tuberculosis has been shown to quickly acquire resistances even to newly developed and last-resort antibiotics within a few years after their introduction into the clinics as well as the occurrence of so-called totally drug-resistant strains [4,5]. These observations together with the host response-driven pathogenesis of active tuberculosis emphasize the need to explore alternative treatment strategies adjunct to antibiotics

Objectives

Methods

Results

Conclusion