Biology subjects

Balakhmet, A.

Publications and source records attributed to Balakhmet, A..

3 recordsLinked to original sources

bioRxiv2026

Dengue virus-specific memory B cell subsets differ as a function of infection history

The four dengue virus serotypes (DENV1-4) are a major global health threat. Infection generates protective immunity over multiple exposures with different serotypes. Virus-specific memory B cells (MBCs) can contribute to lasting protection, yet their development over multiple DENV infections remains undefined. We comprehensively evaluated frequencies of nine DENV-specific B cell subsets in 58 samples from dengue cases, comparing groups with primary (1{degrees}) versus secondary (2{degrees}) DENV infection history. Longitudinal sampling from acute infection to 18 months post-symptom onset enabled assessment of DENV-specific MBC temporal dynamics. Critically, we found that DENV-specific B cell frequency differed substantially at the level of phenotypic subsets in 1{degrees} versus 2{degrees} immunity, despite no significant difference in total frequency of DENV-specific B cells. In particular, DENV-specific IgG+, IgM+, atypical, and class-switched IgD-MBCs were durable until 18 months and accumulated with multiple exposures, representing a bona fide memory compartment against DENV. Also, naive-like IgD+/IgM+ DENV-specific B cells were found. Interestingly, the peak of certain DENV-specific MBCs occurred >3-months post-symptom onset in 2{degrees} DENV immunity, suggesting potential for long-term MBC maturation. We demonstrate that DENV-specific MBC subsets differ as a function of infection history, suggesting that 2{degrees} DENV immunity does not simply generate a quantitative boost, but a qualitative reprogramming of the memory pool. Significance StatementThe four dengue virus serotypes (DENV1-4) cause the most prevalent human mosquito-borne viral disease. Dengue is a febrile disease that often results in debilitating body pain and can rapidly progress to severe disease involving shock. People are generally protected after multiple exposures to different serotypes. Memory B cells (MBCs) can contribute to lasting protection against subsequent dengue. To understand how these rare DENV-specific MBCs develop over multiple exposures, we compared samples from cases with primary versus secondary (i.e., multiple) DENV infections. We found that instead of a higher frequency of total DENV-specific MBCs, particular subsets of DENV-specific MBCs were higher and peaked later after multiple exposures. This suggests that a qualitative shift in DENV-specific MBCs may contribute to protective immunity.

immunology↗

bioRxiv2026

A highly conserved two-gene operon is crucial for lipoarabinomannan localization, pathogenesis, and cell envelope function in Mycobacterium abscessus

Mycobacterium abscessus is an emerging threat, causing infections that are difficult to treat due to intrinsic resistance to most antibiotics. Determinants of M. abscessus physiology and pathogenesis remain poorly understood, hampering therapeutic development. Here, we show that in M. abscessus, the lprg-mfs operon is essential for virulence in macrophages and in mice. Loss of lprg-mfs in M. abscessus causes accumulation of the glycolipid lipoarabinomannan (LAM) on the cell surface and in culture supernatant suggesting that this system participates in LAM import. This contrasts with its proposed role in M. tuberculosis where lprg-mfs has been implicated in the export of various lipids. Consistent with altered lipid distribution, the lprg-mfs mutant displays severe defects in mycomembrane permeability, fluidity, and integrity, and expression of mfs alone restores only a subset of these phenotypes, revealing a surprising uncoupling of envelope fluidity and permeability. Using a suppressor screen to further investigate factors that control the distribution of lipoarabinomannan we find that a point mutation in the unannotated gene MAB_0995 can fully or partially complement all deletion mutant phenotypes. Our data also show that lipoarabinomannan in the mycomembrane is dynamically regulated in response to environmental conditions, including hypoxia and macrophage infection. Together, these findings redefine the role of LprG/Mfs in mycobacterial cell envelope homeostasis and reveal unexpected plasticity in mycomembrane lipid regulation in M. abscessus. ImportanceThe emerging pathogen Mycobacterium abscessus causes life-threatening lung infections in certain patients that are extremely difficult to treat due to its intrinsic resistance to most antibiotics. However, the process by which this organism establishes infection is poorly understood, as are the specific determinants of antibiotic tolerance. Better knowledge of the genes required for virulence and impermeability to antibiotics in M. abscessus could enable to development of more effective treatments. The significance of this study is the demonstration that the lprg-mfs operon is required both for pathogenesis and for impermeability in M. abscessus. Further, our study shows a correlation between cell envelope characteristics and the distribution of the molecule lipoarabinomannan, suggesting a specific mechanism by which these crucial characteristics are mediated.

microbiology↗

bioRxiv2025

Mycobacterium tuberculosis suppresses protective Th17 responses during infection through multiple mechanisms

Mycobacterium tuberculosis (Mtb) causes more deaths annually than any other pathogen, yet an effective vaccine remains elusive. IFN-{gamma}-producing Th1 CD4+ T cells are necessary but insufficient for protection against infection. In humans, the development of IL-17A producing Th17 T cells correlates with protection, however not all individuals develop a Th17 response. In mice, experimental vaccines can elicit protective Th17 cells, yet Th17s are rare in primary infection. Why Mtb fails to consistently elicit Th17s is unknown. Here, we identify factors suppressing Th17 responses during primary infection. We demonstrate that the lack of Th17 induction is independent of route and duration. Next, using Tbet deficient mice, we show that Mtb drives a Th1 response that is only partially protective and limits Th17 cell production in an IFN-{gamma} independent manner. We further reveal that the ESX-1 type VII secretion system and lipid PDIM suppresses Th17 responses. Infection with ESX-1 or PDIM mutants results in significantly increased Th17 T cells and IL-17A cytokine in the lungs, and infection of IL-17A deficient animals partially restores virulence of ESX-1 and PDIM mutants. Although the ESX-1 secretion system and lipid PDIM elicits type I IFN, which can suppress Th17 differentiation, we find that suppression of Th17 is independent of type I IFN. Instead, ESX-1 and PDIM suppresses production of IL-23, a cytokine that promotes Th17 differentiation, in dendritic cells found in mediastinal lymph nodes during Mtb infection. These findings define a new function of the ESX-1 secretion system and PDIM in Mtb virulence, a long-standing question in tuberculosis research.

immunology↗