Drug Resistance Gene Expression Differs between Males and Females in Gonorrhea Infections

June 29, 2018

How do microbes become drug resistant? Some microbes are intrinsically resistant to specific antimicrobials, while others acquire resistance by sharing genetic material or through mutation of their own genome. Once these genetic changes are in place, resistance is often viewed as a binary issue: an infection is caused by either a drug-resistant or a drug-sensitive strain. A new mSphere report suggests that whether a host is male or female is another variable that may affect expression of antibiotic resistance genes. 

mSphere: Transcriptome Analysis of Neisseria gonorrhoeae during Natural Infection Reveals Differential Expression of Antibiotic Resistance Determinants between Men and Women

Neisseria gonorrhoeae is a growing threat both in overall incidence and in drug-resistant cases. A scientific team led by first author Kathleen Nudel and senior scientist Caroline Genco collected and compared the transcriptional profiles of N. gonorrhoeae isolates from males and females. The sexually transmitted disease gonorrhea presents differently depending on sex: while males often experience urethritis that may include purulent discharge, females often have few symptoms until the disease has progressed to pelvic inflammatory disease. The infection itself also differs, since the gonococcus forms a biofilm in females but not in males. Based on this knowledge, the team hypothesized that the bacterium may express different genetic programs in males and females.

Comparing transcriptional responses confirmed these differences and demonstrated that N. gonorrhoeae expresses higher levels of antimicrobial resistance genes, especially efflux pumps, in males (see figure below). In one example, strains from both males and females contained the same mutation in the promoter of efflux pump regulator mtrR; however, the efflux pump itself was expressed significantly more in male but not in female samples.

Expression levels of antibiotic resistance genes in specimens from the male genital tract (blue) or female genital tract (red). *, higher gene expression in men; #, higher gene expression in women. Red and blue Xs indicate the male-female transmission pair.
Expression levels of antibiotic resistance genes in specimens from the male genital tract (blue) or female genital tract (red). *, higher gene expression in men; #, higher gene expression in women. Red and blue Xs indicate the male-female transmission pair.

In another example, the negative efflux pump regulator farR was more highly expressed in female than in male samples, again leading to a lower overall efflux pump expression in bacteria within the female genital tract. This expression pattern was observed in both the average of the 6 male and 7 female specimens examined, as well as the single male-female pair, in which the bacterium had been passed from one sexual partner to another.

Despite these expression pattern differences, strains isolated from both men and women had similar susceptibility patterns, with resistance to penicillin, tetracycline and ciprofloxacin. Single-nucleotide polymorphisms (SNPs) accounted for most of the resistance and were equally distributed between male and female isolates. For example, all strains contained SNPs in gyrA and/or parC, which confers fluoroquinolone resistance. However, male specimens showed decreased expression of pilQ, associated with antibiotic permeability.

Nearly 14% of the total genes expressed by N. gonorrhoeae during infection were differentially regulated in male versus female genital tracts, though these may represent different strategies to adapt to the same environmental stresses. For example, female specimens had higher expression of tonB, which codes for a transporter of iron-scavengers, and male specimens had higher expression of iron-regulated tbpAB, which codes for transferrin binding proteins, but both represent microbial strategies to deal with iron-depleted environments. Similarly, both female and male samples had upregulated oxidative stress genes, though the specific genes differed between the sexes. Not all samples showed similar functional regulation, however: specimens from females had higher expression of 45 different tRNAs than did specimens from men.

Why does N. gonorrhoeae behave differently in infected males and females? The scientists speculate that factors such as genital microflora, biofilm formation or variable niche conditions contribute to the observed differences. Confounding factors, such as antibiotic use by several of the male subjects but none of the female subjects, may also explain the differential regulation of drug resistance-related genes, and the authors plan to follow up this initial study with a larger one to differentiate the important variables. 

Discovery of sex-dependent differences in N. gonorrhoeae transcription adds to the growing number of infectious diseases that behave differently in males versus females. In addition to adding to a generalized understanding of the role of biological sex during infection, should the sex-related resistance differences hold up, these findings may help health care providers to better tailor therapies.

Learn more about biological sex + infection or N. gonorrhoeae with these ASM Resources: 

mBio Editorial: Sex Reporting in Preclinical Microbiological and Immunological Research

Bugs & Drugs Clinical Microbiology Blog Post: When the Clap Hits Back (three-part series)

Author: Julie Wolf

Julie Wolf
Dr. Julie Wolf is in science communications at Indie Bio, and was a former ASM employee. Follow Julie on Twitter for more ASM and microbiology highlights at @JulieMarieWolf.