Biology subjects

Hoffmann, J. P.

Publications and source records attributed to Hoffmann, J. P..

4 recordsLinked to original sources

bioRxiv2026

Intrinsic T-cell programming and immune spatial organization govern sex-biased tuberculosis immunity

Biological sex can profoundly influence the susceptibility to infectious diseases, yet the mechanisms behind the sex-dependent protective immunity against tuberculosis (TB) remain poorly understood. Here we show that sexually divergent immunity during chronic Mycobacterium tuberculosis (Mtb) infection is governed by both intrinsic T cell programming and pulmonary immune spatial organization. Using the Four Core Genotype (FCG) mouse model, adoptive cell transfer, pathway-specific blockade and B cell depletion, we demonstrate that CD4 T cells from gonadal females (XXF), but not XX males (XXM), confer enhanced protection to susceptible XY male recipients, independently of sex chromosome complement. Female-derived CD4 T cells reduce Mtb burdens while promoting pulmonary Bcl6 CD4 T cell responses and limiting neutrophilic inflammation. Mechanistically, blockade of CXCR3 or CD40L abrogates female-associated protection, with CD40L signaling additionally required to maintain organized pulmonary B cell structures. Although depletion of conventional B-2 B cells did not impair bacterial control, it disrupted tertiary lymphoid organization and revealed striking sex-specific functions of pulmonary B cells. Loss of B cell follicles (BCFs) primarily remodeled adaptive T cell responses in females, whereas in males it drove inflammatory myeloid activation, exaggerated neutrophil recruitment and widespread neutrophil extracellular trap (NET) formation. Together, these findings identify two complementary layers of sex-dependent immune regulation during TB: intrinsic programming of protective female CD4 T cells, and B cell-dependent spatial organization that coordinates adaptive immunity in females while restraining pathological inflammation in males. These findings establish immune tissue organization as a key determinant of the sexually dimorphic host defense during chronic TB.

immunology↗

bioRxiv2026

Gonadal regulation of sex-specific immunity in tuberculosis: enhanced lymphocyte function in females and dysfunctional myeloid responses in males

Tuberculosis (TB), the worlds deadliest infection, shows higher prevalence and mortality in males than females (M/F ratio >1.7). Using Four Core Genotype (FCG) mice to decouple gonadal from chromosomal sex (XX, XY gonadal males and XX, XY gonadal females), we show that gonadal males develop accelerated disease driven by dysfunctional myeloid responses rather than impaired bacterial recognition. Both XX and XY males exhibited increased mortality, higher Mycobacterium tuberculosis (Mtb) burden, and severe lung pathology. Mechanistically, gonadal male susceptibility involved early myeloid priming, excessive neutrophil recruitment, CCR2 monocyte accumulation, and hyperinflammation, with enhanced neutrophil extracellular trap (NET) formation and disorganized granulomas, implicating testes and androgens as key drivers of male susceptibility. While XY gonadal females were less susceptible, XX gonadal females showed the greatest resistance, associated with coordinated T- and B-cell responses and enhanced B-cell follicle formation. Together, these findings identify gonad-driven myeloid dysregulation as a central mechanism underlying male TB susceptibility.

immunology↗

bioRxiv2026

Single-Cell RNA Sequencing Reveals Commensal Microbes Amplify Sex-Specific Immune Programming in the Murine Lung

Sex-based differences in respiratory disease outcomes are well recognized. However, the underlying immunological mechanisms driving this dimorphism remain incompletely understood. While sex hormones influence immune cell development and function, the role of commensal microbes in shaping sex-specific lung immunity has not been explored. Here, we used single-cell RNA sequencing (scRNAseq) and flow cytometry to profile lung immune cells in male and female mice housed under specific pathogen-free (SPF) or germ-free (GF) conditions. Under SPF conditions, males exhibited a striking myeloid bias, with increased monocytes and macrophages, along with broad upregulation of inflammatory mediators, including S100a8, S100a9, and Il1b, across multiple cell types, and enrichment of TNF and interferon (IFN) signaling pathways. In contrast, females displayed lymphocyte-skewed profiles, with higher frequencies of T cells and natural killer (NK) cells. Interestingly, these sex-based differences in immune composition and inflammatory programs were largely absent in GF mice, indicating that microbial exposure amplifies baseline immunological dimorphism between males and females. Notably, select sex-associated features, including female-biased NK cell enrichment, persisted irrespective of microbial status, suggesting intrinsic, microbiota-independent programming. Together, these findings indicate that commensal microbes modulate sex-specific lung immunity by amplifying pre-existing intrinsic differences, highlighting the intersection of extrinsic (microbial) and intrinsic (sex-linked) factors in shaping baseline mucosal immunity.

immunology↗

bioRxiv2022

Optimization of host cell-compatible, antimicrobial peptides effective against biofilms and clinical isolates of drug-resistant bacteria.

Here, we describe the continued synthetic molecular evolution of a lineage of host-compatible antimicrobial peptides (AMP) intended for the treatment of wounds infected with drug-resistant, biofilm-forming bacteria. The peptides tested are variants of an evolved AMP called D-CONGA, which has excellent antimicrobial activities in vitro and in vivo. In this newest generation of rational D-CONGA variants, we tested multiple sequence-structure-function hypotheses that had not been tested in previous generations. Many of the peptide variants have lower antibacterial activity against Gram-positive or Gram-negative pathogens, especially variants that have altered hydrophobicity, secondary structure potential, or spatial distribution of charged and hydrophobic residues. Thus, D-CONGA is generally well tuned for antimicrobial activity. However, we identified a variant, D-CONGA-Q7, with a polar glutamine inserted into the middle of the sequence, that has higher activity against both planktonic and biofilm-forming bacteria as well as lower cytotoxicity against human fibroblasts. Against clinical isolates of K. pneumoniae, innate resistance to D-CONGA was surprisingly common despite a lack of inducible resistance in P. aeruginosa reported previously. Yet, these same isolates were susceptible to D-CONGA-Q7. D-CONGA-Q7 is much less vulnerable to AMP resistance in Gram-negative bacteria than its predecessor. Consistent with the spirit of synthetic molecular evolution, D-CONGA-Q7 achieved a critical gain-of-function and has a significantly better activity profile.

biochemistry↗