A protective role for type I interferon signaling following infection with Mycobacterium tuberculosis carrying the rifampicin drug resistance-conferring RpoB mutation H445Y.

Interleukin-1 (IL-1) signaling is essential for controlling virulent Mycobacterium tuberculosis (Mtb) infection since antagonism of this pathway leads to exacerbated pathology and increased susceptibility. In contrast, the triggering of type I interferon (IFN) signaling is associated with the progression of tuberculosis (TB) disease and linked with negative regulation of IL-1 signaling. However, mice lacking IL-1 signaling can control Mtb infection if infected with an Mtb strain carrying the rifampin-resistance conferring mutation H445Y in its RNA polymerase ß subunit (rpoB-H445Y Mtb). The mechanisms that govern protection in the absence of IL-1 signaling during rpoB-H445Y Mtb infection are unknown. In this study, we show that in the absence of IL-1 signaling, type I IFN signaling controls rpoB-H445Y Mtb replication, lung pathology, and excessive myeloid cell infiltration. Additionally, type I IFN is produced predominantly by monocytes and recruited macrophages and acts on LysM-expressing cells to drive protection through nitric oxide (NO) production to restrict intracellular rpoB-H445Y Mtb. These findings reveal an unexpected protective role for type I IFN signaling in compensating for deficiencies in IL-1 pathways during rpoB-H445Y Mtb infection.

Mycobacterium tuberculosis carrying the rifampicin drug-resistance-conferring rpoB mutation H445Y is associated with suppressed immunity through type I interferons.

IMPORTANCE: This study highlights the impact of specific rifampicin-resistance-conferring mutations on the host immune response to Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Clinical reports have previously suggested that multi-drug-resistant) TB patients exhibit altered peripheral immune responses as compared with their drug-sensitive TB counterparts. The murine model of infection with Mtb strains carrying drug-resistance-conferring mutations recapitulated these findings and allowed us to mechanistically interrogate the pathways responsible for driving the divergent immune responses. Our findings underscore the need for greater investigation into bacterial heterogeneity to better appreciate the diversity in host-pathogen interactions during TB disease.

Mycobacterium tuberculosis infection drives differential responses in the bone marrow hematopoietic stem and progenitor cells.

Hematopoietic stem and progenitor cells (HSPCs) play a vital role in the host response to infection through the rapid and robust production of mature immune cells. These HSPC responses can be influenced, directly and indirectly, by pathogens as well. Infection with Mycobacterium tuberculosis (Mtb) can drive lymphopoiesis through modulation of type I interferon (IFN) signaling. We have previously found that the presence of a drug resistance (DR)-conferring mutation in Mtb drives altered host-pathogen interactions and heightened type I IFN production in vitro. But the impacts of this DR mutation on in vivo host responses to Mtb infection, particularly the hematopoietic compartment, remain unexplored. Using a mouse model, we show that, while drug-sensitive Mtb infection induces expansion of HSPC subsets and a skew toward lymphopoiesis, DR Mtb infection fails to induce an expansion of these subsets and an accumulation of mature granulocytes in the bone marrow. Using single-cell RNA sequencing, we show that the HSCs from DR Mtb-infected mice fail to upregulate pathways related to cytokine signaling across all profiled HSC subsets. Collectively, our studies report a novel finding of a chronic infection that fails to induce a potent hematopoietic response that can be further investigated to understand pathogen-host interaction at the level of hematopoiesis.

Rifampicin drug resistance and host immunity in tuberculosis: more than meets the eye.

Tuberculosis (TB) is the leading cause of death due to an infectious agent, with more than 1.5 million deaths attributed to TB annually worldwide. The global dissemination of drug resistance across Mycobacterium tuberculosis (Mtb) strains, causative of TB, resulted in an estimated 450 000 cases of drug-resistant (DR) TB in 2021. Dysregulated immune responses have been observed in patients with multidrug resistant (MDR) TB, but the effects of drug resistance acquisition and impact on host immunity remain obscure. In this review, we compile studies that span aspects of altered host-pathogen interactions and highlight research that explores how drug resistance and immunity might intersect. Understanding the immune processes differentially induced during DR TB would aid the development of rational therapeutics and vaccines for patients with MDR TB.

The nepenthesin insert in the Plasmodium falciparum aspartic protease plasmepsin V is necessary for enzyme function.

Plasmepsin V (PM V) is a pepsin-like aspartic protease essential for growth of the malarial parasite Plasmodium falciparum. Previous work has shown PM V to be an endoplasmic reticulum-resident protease that processes parasite proteins destined for export into the host cell. Depletion or inhibition of the enzyme is lethal during asexual replication within red blood cells as well as during the formation of sexual stage gametocytes. The structure of the Plasmodium vivax PM V has been characterized by X-ray crystallography, revealing a canonical pepsin fold punctuated by structural features uncommon to secretory aspartic proteases; however, the function of this unique structure is unclear. Here, we used parasite genetics to probe these structural features by attempting to rescue lethal PM V depletion with various mutant enzymes. We found an unusual nepenthesin 1-type insert in the PM V gene to be essential for parasite growth and PM V activity. Mutagenesis of the nepenthesin insert suggests that both its amino acid sequence and one of the two disulfide bonds that undergird its structure are required for the insert's role in PM V function. Furthermore, molecular dynamics simulations paired with Markov state modeling suggest that mutations to the nepenthesin insert may allosterically affect PM V catalysis through multiple mechanisms. Taken together, these data provide further insights into the structure of the P. falciparum PM V protease.

Inflammatory comorbidities: to train or not to train?

Inflammatory stimuli reprogram innate immune cells to generate rigorous responses to future challenge with heterologous stimuli through trained immunity. Li et al. show that training of hematopoietic stem cells (HSCs) in the bone marrow primes cells to generate more inflammatory myeloid progeny and, thereby, mechanistically links inflammatory comorbidities.

Mycobacterium tuberculosis HN878 Infection Induces Human-Like B-Cell Follicles in Mice.

Specific spatial organization of granulomas within the lungs is crucial for protective anti-tuberculosis (TB) immune responses. However, only large animal models such as macaques are thought to reproduce the morphological hallmarks of human TB granulomas. In this study, we show that infection of mice with clinical "hypervirulent" Mycobacterium tuberculosis (Mtb) HN878 induces human-like granulomas composed of bacilli-loaded macrophages surrounded by lymphocytes and organized localization of germinal centers and B-cell follicles. Infection with laboratory-adapted Mtb H37Rv resulted in granulomas that are characterized by unorganized clusters of macrophages scattered between lymphocytes. An in-depth exploration of the functions of B cells within these follicles suggested diverse roles and the activation of signaling pathways associated with antigen presentation and immune cell recruitment. These findings support the use of clinical Mtb HN878 strain for infection in mice as an appropriate model to study immune parameters associated with human TB granulomas.