Archive for the ‘Bacterial vaginosis’ Category

Presence of BV-related bacterial species in the vaginal microbiota may contribute to the vulnerability of African women to HIV

Thursday, February 15th, 2018

The association between disruptions of vaginal microbiota and vulnerability to STIs has been widely discussed. Tamarelle & Astagneau (STI) report a study based in a French STI clinic showing some evidence of greater vulnerability to Chlamydia in the case of microbiota not dominated by Lactobacillus crispatus. The more important question of an association of BV-related bacteria with vulnerability to HIV has been in the air for a long time (Schmid & Koumans (STI))Gosmann & Kwon, in a recent study of South African women showed a four-fold decreased vulnerability among women with L. crispatus-dominated microbiota compared with women with microbiota dominated by non-Lactobacillus communities other than Gardnerella.

Now McClelland & Fredericks (M&F) have reported a study of vulnerable South and East African women based on five cohorts assembled for the purposes of some recent well known HIV studies, including Partners in Prevention and Partners PrEP. These included sex-workers, women in sero-discordant relationships and pregnant or post-partum women. The two-stage design involved: first, using abundance data to show the association of bacterial diversity with HIV and to guide selection of bacteria for further investigation; second, testing the hypothesis of an association of concentrations of each of twenty selected bacteria with HIV risk by subjecting vaginal samples from 55 HIV infected and 55 HIV non-infected women to taxon-directed rtPCR assays. In the studies mentioned earlier, associations are sought not with individual taxa, but with five or so overall microbiota types.

C&F found bacterial diversity to be higher in HIV infected women: median 1.3 as against 0.7. There were significant associations with HIV acquisition for seven of the 20 bacterial taxa; for the third tertile of concentration, adjusted odd ratios for HIV association were: Parvimonas species type 1, 4.64; P. species type 2, 2.18; Gemella asaccharolytica, 3.03; Mycoplasma hominis, 2.76; Leptotrichia/Sneathia, 2.59; Eggerthella species type 1, 1.53; vaginal Megasphaera, 1.32. As might be expected from the earlier studies mentioned above, there were strongly correlations in the concentrations of many of the 20 taxa, excluding the lactobacilli (crispatus; iners; jensenii).

There has been some debate in the literature about whether the greater vulnerability associated with certain microbiota types has more to do with the presence of disruptive bacteria or a deficiency of protective lactobacilli. M&F note that their primary analysis using rtPCR assays in the full dataset showed no significant association between concentration of lactobacilli and HIV acquisition. So, in the light of the negative correlation between concentrations of lactobacilli and BV related bacterial species, they are inclined to favour the view that increased susceptibility to HIV is the result of the presence of disruptive bacteria rather than the deficiency of protective ones.

On a more general level, M&F see their study as suggesting an explanation of the apparently much greater vulnerability of African women to HIV infection than women of European and Asian origin: higher diversity vaginal bacterial communities not dominated by lactobacilli are more common in this racial group. M&F suggest that vaginal dysbiosis may account for as much as 20-30% of the population attributable risk of HIV acquisition in African women.

Boys’ BV?

Monday, September 4th, 2017

Recent studies in STIs have drawn attention to the impact of the state of the microbiome of the female genital tract (FGT) and susceptibility to STIs – and, in particular, the protective effect of the hydrogen peroxide-releasing microbe Lactobacillus crispatus (L.c.) (Antonio & Hillier/STIs) (A&H). Such STIs include, not only BV (53% less likely with L.c., according to A&H), but apparently also HIV, gonorrhea and HSV-2, which show, according to a Uganda based study (Francis & Grosskurth/STIs) an association of BV estimated at RR 2.35, 1.3, 1.69, respectively. A recent study of 236 young women participating in the S. African FRESH cohort found that, of the 24 of these having a FGT microbiome dominated by L.c., none figured among the 31 HIV seroconversions (STI blogs: Susceptibility of sub-Saharan women to HIV). Haggerty & Ness/STIs (http://sti.bmj.com/content/92/6/441?sid=674668c5-6489-4db7-8da7-dc541da48ec8), in the PID Evaluation and Clinical Health Study, find a strong (RR 4.7) association of certain FGT microbiotic bacteria with PID. Finally, a mouse based study by Gilbert & Lewis (STI/blogs: Bacterial vaginosis associated bacterium) seems to confirm the hypothesis, proposed in 2001 by Shahmanesh/STIs (http://sti.bmj.com/content/77/2/139), that Gardnerella may indirectly cause NGU (non-gonococcal urethritis) by triggering the emergence of covert Escheridia coli.

But if the importance now seems established of the composition of the woman’s FGT microbiome for the susceptibility to a whole range of STI (BV, HIV, Ng, HSV-2, PID, NGU), what are we to think of the finding of a recent paper in mBio (the journal of the American Society for Microbiology) that bacteria in the penile microbiome play a comparable role in the case of men – at least, in respect to HIV?

Liu & Price  http://mbio.asm.org/content/8/4/e00996-17.abstract?related-urls=yes&legid=mbio;8/4/e00996-17) uses data from 182 uncircumcised men from Rakai, Uganda, 46 of whom go on, over a two-year period, to develop HIV. In the case of five genera of bacteria suspected of playing a role in the association between male circumcision and reduced HIV risk, a strong association was discovered between their baseline prevalence in the penile microbiome and the risk of infection with HIV. With each 10-fold increase in the abundance of Prevotella, and Diliaster, for example, an increased risk was noted (AOR: 1.63 and 1.57, respectively). Other genera associated with increased risk were Peptoniphilus, Finegoldia, Porphyromonas, Mobiluncus, Peptostreptococcus, and Murdochiella. HIV risk was also found to be associated with inflammatory markers – especially interleukin-8. Presence of the latter increased significantly with densities of anaerobic bacteria. The greatest risk was observed where three are more cytokines were detected. These findings lead the researchers to conclude that the response of the immune system to shifts in the penile microbiome facilitate infection by HIV.

Of course, this is precisely the mechanism that may account for the increased susceptibility to STI (including HIV) in women with FGT deficient in L.c.. However, the problem can be largely resolved in the case of men by means of circumcision.

The authors also make the interesting point that the bacterial dysbiosis that they observe in the male microbiome may be passed on to women through sexual activity – so that the genital microbiome is, to some extent, ‘shared’ between them. Presumably, this could also mean that voluntary male medical circumcision reduces this risk of HIV transmission for women as well as men to the extent that women are at less risk of infection with bacteria that render them susceptible to HIV.

Bacterial vaginosis-associated bacterium (Gardnerella) may after all have a role in the aetiology of non-gonococcal urethritis

Friday, April 28th, 2017

The question of the aetiology of ‘non-gonococcal’ or ‘non-specific’ urethritis (NGU/NSU) has been a hot topic of debate in this journal and its predecessors since before 1951, when it was officially acknowledged in the Chief Medical Officer’s report as an independent category of infection (Oriel (STI)). More recently, a number of infectious agents have been recognized as potentially responsible (Hallen & Wallin (STIs); Moi & Moghaddam (STIs)).  But it would be misleading to suggest that, even today, the aetiological question has been altogether resolved.

The controversial hypothesis that bacterial vaginosis (BV) associated bacteria (i.e. Gardnerella) might have a role – proposed in 2001 in an STI editorial by a former editor (Shamanesh (STIs)) – seems to have raised its head once again in a recent animal-based study, Gilbert & Lewis (G&A). Results from studies that have tested for the presence of these – amongst other – bacterial agents seem not to have been particularly favourable to the hypothesis (Manhart & Fredericks (STI); Froelund & Jensen (STIs)).  It must be borne in mind, however, that ‘fastidious growth requirements make G. vaginalis unrecoverable, or at least unidentifiable, under conditions most often used by clinical microbiology labs for the culture and identification of potential uropathogens’ (G&A, p.11).

G&A hypothesize G. vaginalis operates indirectly in the case of NSU by triggering the emergence of Escherichia coli from reservoirs in the bladder of the pre-infected individual.  In this way repeated sexual contact could, they suggest, lead to recurrent UTI infections by an infection that is not itself sexually transmitted.  This theory of ‘covert pathogenesis’ is tested by exposing mice with latent E-coli infection – i.e. mice that had been transurethrally pre-infected but were now negative for bacteriuria – to repeated doses of G. vaginalis or Lactobacillus crispatus.  It was found that double exposure to G.v. triggered E-coli bacteriuria while exposure to L.c.  did not.  Furthermore, G.v. exposed mice had neutrophilic infiltrates, confirming the presence of active UTI.  In sacrificed mice, G.v. was also found to have induced bladder epithelial exfoliation and apoptosis in the bladder epithelium.

The theory of covert pathogenesis is intriguing – not least because it overrides any hard-and-fast distinction been sexually-related and non-sexually-related UTIs.  But, assuming it turns out to be correct, it also has practical implications.  The conventional paradigm assumes that the pathogen present at time of clinical presentation is the main driver of disease.  Given the alarming rise of multi-drug resistant E-coli, the authors point to the potential benefit of preventing UTI and sequelae (e.g. pyelonephritis) by targeting the organism that triggers the infection (i.e. G. vaginalis) rather than the pathogen that causes the symptoms.

 

Susceptibility of heterosexual sub-Saharan women to HIV could be the result of cervicovaginal microbiome characteristics

Monday, January 30th, 2017

Could part of the explanation for the apparent susceptibility of sub-Saharan African heterosexual women to HIV infection (eight-fold that of males) lie in the bacterial flora of their female genital tract (FGT)?

Studies published in STI journal have considered the relationship between a certain state of the FGT bacterial microbiome – especially the depletion of lactobacillus (Francis & Grosskurth/STIs) – and the susceptibility to BV (Antonio & Hillier/STIs; Hardy & Crucitti/STIs; Francis & Grosskurth/STIs; Haggerty & Ness/STIs), to pelvic inflammatory disease (Haggerty & Ness/STIs), and to other STIs (Francis & Grosskurth/STIs).  Others have observed the prevalence of Lactobacillus in the healthy FGT microbiome (Madhivanan & Krupp/STIs), and considered the impact on the FGT lining of practices of vaginal douching (Balkus & McClelland/STIs), hormonal contraception (Verwijs & Wijgert/STIs), and sexual debut (Jespers & Crucitti/STIs).

Highly relevant to all these discussions is a recently published study by Gosmann & Anahtar of a prospective cohort of 236 young HIV-negative women participating in the South African Ragon Institute’s FRESH study (Females Rising through Educations, Support and Health) in Kwa-Zulu Natal. The researchers were able to follow up their cohort for a total of 198.2 person-years, in the course of which 31 participants acquired HIV.  The researchers distinguish four ‘cervicotypes’ in respect to FGT bacterial flora; then determine their prevalence along with their association with ‘HIV target cells’ (i.e. activated CD4 T cells expressing the HIV co-receptor CCR5) and HIV acquisition.

The four cervicotypes correspond to the dominance of Lactobacillus crispatus and of Lactobacillus iners (CT1 and CT2, respectively), the preponderance of Gardnerella vaginalis (CT3), and a biome showing a far more diverse range of bacterial types (CT4).  Strikingly, the first two cervicotypes (CT1 and CT2) account for only 10% and 32% of women in the cohort; while, among white women in Western countries, the proportion showing Lactobacillus dominance would be c.90%.  The other 58% fall into the categories of high diversity communities with low Lactobacillus abundance (CT3 and CT4).  More interestingly still, none of the 31 HIV sero-conversions took place among the 10% of women with CT1-type bacterial flora.  Rather, sero-conversions were fairly evenly distributed among the other three cervicotypes, with some diminution of relative incidence in the CT2 category (i.e. nine sero-conversions, as opposed to 10 and 12 in CT3 and CT4 respectively).  Researchers observed a 17-fold increase in HIV target cells in women with a CT4-type cervico-vaginal microbiome as against those with CT1-type, and elevated levels of chemokines MIP-α and MIP-β which attract CCR5 expressing cells in women with diverse FGT bacterial communities.

Sadly, regimens aiming to restore Lactobacillus crispatus dominance (e.g. antibiotics or probiotic vaginal suppositories) show significant recurrence rates.  However, modifiable biological and behavioural factors may play a considerable role on Lactobacillus depletion in sub-Saharan African women (e.g. vaginal washing; antibiotic use; recent Trichomonas and HSV-2).  If so, then, as Baeten & McClelland/STIs point out, this would suggest the possibility of effective intervention strategies to reduce HIV transmission by improving vaginal health.