Belmonte, R. L. | bioRxiv Science

bioRxiv2025

Different ways to die: harnessing variation in Drosophila reveals loss of tolerance and resistance over age and sex-specific association between infection susceptibility and lifespan

It is widely accepted that susceptibility to infection increases with age. The reason often invoked is the dysregulation of the immune system, which is both cause and consequence of ageing. However, we do not all age in the same way, and increased susceptibility may not be solely due to immune dysregulation affecting resistance to infection. There are many possible ways to make a host less tolerant to infection by dysregulating key physiological or metabolic processes. We hypothesised that the increase in susceptibility to infection over age can be linked to both immune ageing and decreased tolerance, and importantly, that it will depend on genotype and sex of the host. We assessed susceptibility to Gram-negative bacterial challenge in both sexes in 22 Drosophila isolines at young and old ages, and leveraged variation between genotypes to investigate how frequently an increase in susceptibility to infection was more associated with a decline in resistance or disease tolerance mechanisms. To achieve this, we assessed pathogen load to report on host immune decline. Strikingly, in most cases, greater infection susceptibility at old age was driven by reduced tolerance, although we also frequently identify cases that suffered bona fide immunosenescence, e.g. impaired resistance. We screened across bacterial pathogens during systemic and oral infections and found sex-specific signatures in survival in young and old individuals, but increased susceptibility with age occurred in both sexes. Pairing infection survival with lifespan data, we find that transcending genotype variation, susceptibility at old age predicts lifespan in males only, regardless of the existence or direction of sex bias in longevity. This work highlights that increased infection susceptibility is an early-arising ageing phenotype that occurs in both sexes, but only predicts lifespan in males, paralleling burgeoning evidence in mammals for male-biased effects of age on infection and its connection with mortality. Our data support a model where infection susceptibility increases with age following the same multiplicative pattern as organismal mortality, with existing failures making new failures more consequential. We propose that the term "immunosenescence" be used specifically to describe proven dysregulation of immune tissue resistance mechanisms. We argue that to fully understand the drivers of age-related susceptibility to infection, it is essential to consider genotype, sex, and their interaction, as well as the dysregulation of non-immune functions that influence the ability to control pathogens.

immunology↗

bioRxiv2025

Cochlin-Expressing Memory B (COMB) Cells Are Enriched in Autoimmune Diseases and Display a Distinct Activation Profile

Rheumatoid arthritis (RA) is the most common chronic autoimmune arthritis, causing joint damage and affecting multiple organs over time. B cells play a key role in driving the disease by producing autoantibodies, releasing cytokines, and presenting antigens to T cells. While B cell depletion therapies can help reduce inflammation, they remove all CD20+B cells indiscriminately, which can increase infection risk and interfere with important regulatory immune functions. To better define pathogenic B cell subsets, we performed single-cell RNA and ATAC sequencing on circulating and synovial B cells from patients with early, untreated RA. We identified a novel population of memory B cells expressing cochlin (COCH), termed cochlin - expressing memory B (COMB) cells. While detectable at low levels in healthy controls, COMB cells are significantly expanded in RA and exhibit a distinct transcriptional profile indicative of immune activation. Epigenetic analysis showed that COMB cells have more open chromatin at key immune regulatory regions, including sites bound by NF-{kappa}B family transcription factors like RELA and REL. This suggests that these cells are primed to respond to inflammatory signals. We also looked at publicly available datasets and found COMB-like cells in the blood of people with systemic lupus erythematosus (SLE) and Sjogrens syndrome (SjS), as well as in inflamed kidney tissue from patients with SLE. COMB cells across these diseases share a conserved gene expression signature, pointing to a common memory B cell programme associated with autoimmunity. These findings define COMB cells as a previously unrecognised, transcriptionally and epigenetically distinct memory B cell subset enriched across autoimmune diseases, offering new insights into B cell-mediated pathology and potential therapeutic targets.

immunology↗