Bacterial vaginosis (BV) is an awfully common—and awful—condition that impacts 1/4 to 1/3 of women worldwide in their lifetime. BV is triggered when the vaginal microbiome, which is normally dominated by acid-loving Lactobacilli species, becomes overrun with other microbes. These party crashers cause pH changes, irritate the tissues and local immune system, and stimulate mucosal-irritating inflammation (which some species use to their advantage).
BV is painful, itchy, and is the most common reason women seek gynecological care. More than that, BV can lead to severe medical conditions including preterm delivery or endometriosis. To add insult to injury—or rather, infection to injury—BV also increases the risk of invasion by sexually transmitted pathogens such as HIV.
BV can impact the entire cervicovaginal tract (CVT), which comprises the vagina and ectocervix. Like all of our mucosal membranes, the CVT is patrolled by highly specialized immune cells that act as the first line of defense against invaders. For example, tissue resident memory T cells are different than those that circulate in the blood; this subtype of T cells express unique activation markers or other factors which help them maintain tissue residency, and they can sometimes be especially inflammatory during chronic infections. Upon recognition of their specific antigen, they then secrete cytokines to promote inflammation and chemokines to recruit other T cells for backup.
This T cell response is an essential defense against pathogens, but this is a double-edged sword, as an important subclass of T cells are the target cells for HIV infection. In the context of BV, it’s been hypothesized that higher numbers of T cells expressing essential HIV co-receptors CD4 and CCR5 at the vaginal lumen explains increased risk of HIV infection.
“Previous studies have led to hypotheses for the biological mechanisms for increased HIV susceptibility in those with BV,” says Finn MacLean, a former research technician in the Lund Lab who is starting medical school in the fall. However, different studies have inconsistent findings: some studies have found increased numbers of CD4+CCR5+ HIV target cells in vaginal swabs of people with BV compared to those without, but this finding has not been consistently replicated. This suggests the answer may not be that easy, and that more complex factors may be at play.
MacLean is the lead author on a new study published in The Journal of Clinical Investigation that looked to comprehensively evaluate how BV impacts the immunological profile in the CVT. To do this, he worked with other members of the Lund Lab, the University of Washington International Clinical Research Center, and colleagues in Thika, Kenya to collect samples from women in sub-Saharan Africa with or without BV. “HIV and BV are both highly prevalent in Kenya and other regions of sub-Saharan Africa, making this adverse outcome of particular concern among our study cohort,” MacLean says.
A key difference between this study and previous studies was sampling methodology: to understand the immune state in deeper tissue layers, it was necessary to take cervical and vaginal tissue biopsies rather than rely on minimally invasive sample collection techniques like vaginal swabs or cytobrushes (what’s used for pap smears). These samples were then analyzed by high-throughput flow cytometry to broadly characterize what populations of immune cells were present and by immunofluorescence to understand where these populations were located in the tissue.
Via flow cytometry, the authors found increased proportions of HIV target cells in the cervix samples of participants with BV. However, this observation was not recapitulated by the immunofluorescence data, as there was no increase in HIV target cell density in cervical or vaginal tissues during BV. Like the discrepancies between other previous studies, this strongly suggests that there’s no consistent, obvious increase in HIV target cells in the CVT that can easily explain why people with BV have increased susceptibility to HIV.
What the authors found instead was that T cells in the CVT tended to express more markers of activation and dysfunction. One that particularly stood out was CD39, which is associated with decreased vaccine response and increased likelihood of programmed cell death. Another subset of T cells also expressed more markers of exhaustion that are known to arise due to chronic activation. BV can be a recurring condition, and these findings suggest that constant immune activation in chronic BV may be detrimental to immune health in the CVT.
Additionally, the authors found that levels of T cell-recruiting chemokines were actually reduced in BV samples even though inflammatory cytokines were increased. This further strengthens the authors’ argument that the immune response becomes dysregulated during BV.
Together, these observations indicate that BV throws the mucosal immune system into disarray. This could inhibit the T cells’ ability to perform antiviral functions and may explain the increased risk of infections. “We believe that the immune dysfunction, which may relate to the often recurrent and persistent nature of BV, may inhibit the host’s natural ability to defend itself against viral exposures,” concludes MacLean.
In the future, the authors want to follow up on whether this dysfunctional immune phenotype is related to how frequently people get BV: i.e., what does the immune response look like for those experiencing their first bout of BV compared to those who’ve had BV several times? Understanding how BV weakens mucosal immunity could give us a clue on how to better treat BV and its assortment of adverse outcomes.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium members Michelle Sabo and Nelly Mugo contributed to this research.
The spotlighted research was funded by the National Institute of Allergy and Infectious Diseases.
MacLean F, Tsegaye AT, Graham JB, Swarts JL, Vick SC, Potchen NB, Cruz Talavera I, Warrier L, Dubrulle J, Schroeder LK, Saito A, Mar C, Thomas KK, Mack M, Sabo MC, Chohan BH, Ngure K, Mugo NR, Lingappa JR, Lund JM; Kinga Study Team. 2025. Bacterial vaginosis associates with dysfunctional T cells and altered soluble immune factors in the cervicovaginal tract. J Clin Invest. ;135(10):e184609.
Hannah Lewis is a postdoctoral research fellow with Jim Boonyaratanakornkit’s group in the Vaccine and Infectious Disease Division (VIDD). She is developing screens to find rare B cells that produce protective antibodies against human herpesviruses. She obtained her PhD in molecular and cellular biology from the University of Washington.
For the Media