How does staphylococcus reproduce

The interaction between SIF and spermatozoa is also ligand-receptor dependent. Interestingly, SIF has been found to impede motile bacteria, in addition to sperm, such as E. The molecular mimicry of SIF receptor has been confirmed between spermatozoa and bacteria [ 35 ]. In addition to the effector molecules mentioned above, some novel mechanisms responsible for the staphylococcal regulation of sperm have now been discovered.

A recent study on the semen of infertile males indicated that other virulence genes in S. Berktas et al. It has been demonstrated that BV is the most common lower genital tract disorder among women of reproductive age. In particular, staphylococcal infection is presumed to be a contributing factor for the adverse pregnancy outcomes and female infertility. Staphylococcal infection causes malodorous vaginal discharge and is causally associated with sexually transmitted infections.

Also, it has been implicated in the development of endometritis endometriosis , another crucial factor to female infertility. It can affect reproduction at the level of the hypothalamus, pituitary gland, or gonads. Nonetheless, the major impact is thought to occur within the brain or the pituitary gland [ 39 ].

Bacterial endotoxins can trigger the release of cytokines and other immune mediators in the hypothalamus, where the luteinizing hormone LH -releasing hormone and gonadotropin-releasing hormone GnRH neurons are located [ 40 ].

Numerous in vitro and in vivo studies showed that the immune stress and the subsequent action of proinflammatory cytokines have a profound impact on the secretory activity of GnRH and LH neurons in the hypothalamus [ 41 ]. These interconnections between the immune and the neuroendocrine systems are suggested to be based on the mutual sharing of receptors and mediators.

The released cytokines and chemokines then act on the pituitary gland and reproductive organs, which may finally lead to menoxenia, irregular ovulation, and infertility. Evidences have shown that staphylococcal infection generates a large quantity of cytokines in female reproductive system.

These mediators have an important role in the control of reproductive neuroendocrine, ovarian physiology, fetal implantation and development, and placenta function. Female mammals are born with a finite number of oocytes that gradually decreases during prepubertal development and adult life [ 43 ]. Each oocyte is encircled by somatic granulosa cells GCs to form the basic functioning unit of the ovary—the follicle. The size of the oocytes at birth and the rate of endowment depletion dominate the ovarian functional lifespan.

On the other hand, programmed cell death apoptosis has been considered one of the most prevalent mechanisms that contribute to the age-related exhaustion of oocytes. Therefore, a precise balance has to be achieved between prosurvival and proapoptotic molecules to maintain the final destiny of the follicle [ 44 , 45 ].

Recent studies suggest that the inflammatory stress caused by staphylococcal infection may also affect ovarian reserve and cyclicity in women. Proinflammatory reaction, such as its correspondent neurotransmitter secretion, inflammatory gene transcription, and signaling pathway activation, was thought to play essential roles in the process.

Moreover, the production of neurotransmitter, such as sphingolipid ceramide, further acts as a second messenger to promote age-related apoptosis of oocytes. Evidence showed that lower ceramide levels observed in acid sphingomyelinase-deficient mice resulted in a larger postnatal pool of oocytes compared with their wild-type counterparts.

Conversely, Bax-null female mice exhibited to extend the ovarian lifespan [ 46 ]. These data may provide novel perspectives on the regulation of oocyte dynamics by bacterial infection and link the critical biological processes such as infection, inflammation, cell survival, and female fertility.

BV is a polymicrobial syndrome mainly due to an imbalance of vaginal microbiota. Colonization and proliferation of staphylococci is supposed to be one of the reasons for the increase in pathogenic bacteria, anaerobic bacteria, or microaerophiles.

During the pathogenesis of BV, the overgrowth of anaerobes promotes the production of noxious substances, such as polyamines and other compounds. BV can directly affect congenital formation and female fertility as an ascending dissemination of the related bacteria species proved to cause tubal factor infertility.

Another complication accompanied by vaginal staphylococcal infection is chronic endometritis CE , a local inflammatory disease characterized by unusual plasmacytic infiltration in the endometrial stromal areas [ 48 ]. CE frequently happens in the later stage of the infection or under repeated infection. It tends to be neglected in gynecologic practice because of its less apparent symptom and the requirement of time-consuming histopathologic examinations.

In most cases, the diagnosis is made based on gynecological indications, such as abnormal uterine bleeding AUB and infertility [ 49 ]. It is suggested that the infection and inflammation alter the endometrial cytokine profiles, which may further impair endometrial function and lead to menstrual abnormalities and reduced embryo receptivity [ 51 ].

Moreover, the proteomic analysis identified the key signaling pathways involved in inflammation and oxidative stress are closely related with carcinogenetic processes. These studies associate the onset of CE with female infertility, obstetric and neonatal abnormity, and complications. The altered endometrial gene expression may explain the impaired endometrial receptivity and endometrial hyperplastic lesions observed in women affected by CE [ 52 ].

In rodents and humans, implantation is the first coordinated encounter between mother and baby. The abnormal implantation and placentation may lead to various dysfunctions throughout the pregnancy. Pre-eclampsia PE is a pregnancy-induced disorder characterized by hypertension and proteinuria. The etiology of PE still remains poorly understood, but abnormal placentation is proved to be a major reason for this disease. In addition, local infection and immune responses are critically involved in the process of implantation [ 54 ].

Increased placental secretion of proinflammatory cytokines as well as the angiogenic regulators has been implicated in the widespread maternal endothelial dysfunction and the development of PE. It has been shown that cytokines produced within the uterine microenvironment can alter trophoblast action [ 55 ], impair implantation, and placenta vascularization, which may account for the recurrent miscarriage in women [ 56 ].

Elevated circulating IL levels, proportional to severity of diseases, have been detected in the serum of PE mothers when compared with healthy controls [ 57 ].

Also, IL is also proved to be a contributing factor for the impaired trophoblast invasion, spiral artery remodeling, and altered placental labyrinth morphology. These functional abnormities further lead to the development of PE-like features, such as elevated systolic blood pressure SBP , proteinuria, and kidney glomerular pathology. Besides this, decidual natural killer dNK cells, the predominant immune cell, coincide with the decidualization at the maternal-fetal interface in human and mice.

More importantly, vaginal Staphylococcus infection, an infectious agent frequently observed in the uterus, may participate in the development of implantation disorder presumably by the induction of local immune reaction. Antibiotic strategy is considered the most potential therapeutic methods against staphylococcal infection and the resultant infertility.

However, the emergence of antibiotic resistance has dramatically increased in the past two decades and becomes a serious threat to the worldwide public health. In particular, S. The introduction of penicillin in the early s significantly reduced fatal invasive staphylococcal infection.

However, the resistant strains, mostly S. It can effectively block the synthesis of bacterial cell walls by inhibiting the peptidic cross-linkage between the linear peptidoglycan polymer chains.

Therefore, the antibiotic destroys the integrity of the cell wall and selectively kills Gram-positive bacteria. Resistance is generally conferred by the acquisition of the mecA gene, which encodes a PBP2a. Vancomycin belongs to the glycopeptide antibiotic class and is effective in treatment of serious infections caused by Staphylococcus. It is one of the main resources for combating infections caused by MRSA but is not recommended to treat the disease caused by methicillin-sensitive S.

Vancomycin is a complex compound consisting of a branched tricyclic glycosylated peptide and is a rare example of a halo-organic natural compound containing two covalently bonded chlorine atoms. The bactericidal activity of vancomycin is associated with its ability to bind at the D-Ala-D-Ala dipeptide terminus of the nascent peptidoglycan in Gram-positive bacteria and thereby to inhibit the peptidoglycan synthesis [ 60 ].

Common side effects associated this antibiotic involve pain in the area of injection and allergic reactions, and problems with hearing, low blood pressure, or bone marrow suppression occasionally occur. The strain with the reduced susceptibility to vancomycin VISA was first described in , and the alteration of the D-Ala-D-Ala dipeptide was supposed to be the main reason underlying this resistance.

Linezolid has been used for treatment of serious infections caused by Gram-positive bacteria that are resistant to other antibiotics such as MRSA. Means and standard deviations from triplicate experiments are shown.

The dashed line indicates a quadratic polynomial regression fit, and the R 2 and P value for the regression equation are shown. Mutation accumulation experiments combined with genome sequencing are thought to provide the least biased, most realistic, genome-wide mutation rates for bacteria [ 44 , 45 ]. We found that mutation rates from two unrelated strains of MRSA were 2. Hence, they were very similar to previously reported mutation rates from wild-type E.

In contrast, our fluctuation analyses yielded mutation rates per nucleotide in the gene rpoB that were two-fold to three-fold lower. Lower rates from classical fluctuation analyses compared to mutation accumulation are a common observation and have been ascribed to phenotypic delay of antibiotic resistance [ 41 , 47 ]. Nevertheless, results from our fluctuation analyses indicated that mutation rates were independent from methicillin-resistance and similar among diverse S.

Of note, the genome sequence from this isolate did not carry any inactivating mutations in genes involved with DNA replication, DNA repair or recombination, which could cause a mutator phenotype [ 48 ].

Hence, the reasons for elevated mutation rates in this and in another S. Our fluctuation analyses also indicated low variation among mutation rates from multiple isolates of K. Overall, mutation rates from fluctuation analyses were similar among S. This finding is in line with mutation accumulation results for S.

Importantly, these results indicate that the striking, up to fold differences in annual evolutionary rates between these species are not caused by differential mutation rates. The observation of largely uniform mutation rates from diverse S.

Interestingly, a higher evolutionary rate had been found in one study on clonal lineage ST, with confidence intervals not overlapping with those from most other lineages Table 1. Our results suggest this may be caused by an elevated, initial mutation rate in some strains affiliated to this population Fig. Our results suggest rapid and continuous bacterial cell replication particularly during nasal colonization, rather than infection.

This is because annual evolutionary rates and inferred replication rate estimates represent average values for large populations, each of which had been sampled for population genomic analyses over several years, from numerous individual hosts, and across large geographic regions [ 34 , 35 ].

Base substitution rates had been inferred from branch lengths in phylogenetic trees, which represented time spans of several years. Over long time periods, nasal colonization is the dominant lifestyle of S. Therefore, evolutionary rates mostly represent asymptomatic colonization, even though the majority of genome-sequenced isolates may have been collected from infected patients.

The ratio of sequencing coverage between the origin and terminus of replication peak-to-trough ratio, PTR was recently proposed as a proxy for measuring bacterial growth rates in vivo [ 8 , 9 ]. The median PTR was 1. While PTR was used before to assess bacterial growth and compare it among different samples and across bacterial species [ 8 , 9 ], a calibration of PTR to yield generation-time estimates from metagenomic sequence data had not previously been attempted.

Hence, the majority of calibrated PTR measurements suggested about two-fold slower cell division rates than inferred from the ratio of evolutionary rate to mutational rate. After all, even the PTR approach yielded average measurements from population samples of bacteria, whereas replication rates may have been heterogeneous at a single cell level [ 51 , 52 ].

In addition, shedding dynamics on the posterior nasal mucosa are higher than on the squamous epithelia of the anterior nares [ 14 ]. For sampling bacteria from the posterior nasopharynx, however, nasal washing or brushing would be necessary, which is considerably more uncomfortable for participants than nasal swabbing.

Recruitment of volunteers would therefore be more difficult and anonymous self-sampling would not be readily possible. The spontaneous mutation rate of an organism is commonly considered a near-constant trait [ 45 , 53 ]. Therefore we assumed that the spontaneous mutation rate measured in vitro was a reasonably accurate approximation of the mutation rate in vivo.

Some dependency of the mutation rate on environmental conditions cannot be fully excluded, however, and if the mutation rate was higher in the nose than in vitro, our inference would overestimate the in-vivo cell division rate. For example, exposure to antibiotics at subinhibitory levels was reported to increase mutagenesis either through bacterial production of reactive oxygen species that may directly damage DNA [ 54 ], or through a cellular stress response that results in upregulation of a DNA polymerase with reduced replication fidelity [ 55 ].

However, even though the exposure of bacteria to low concentrations of antibiotics is a plausible scenario due to widespread usage of antibiotic drugs, it is not known if such pollution is sufficiently pervasive to have a measurable effect on average mutation rates in natural S. Commonly, cultivation conditions were reported to have little effect on the bacterial mutation rate [ 42 , 44 , 61 ]. Indeed, the fairly good match between our generation time estimates based on evolutionary rates and those directly measured in nasal swabs suggests that S.

Our replication rate estimates are consistent with previously reported in vitro measurements of S. However, the maximum staphylococcal growth rate in the human nasal cavity will depend on the local flux of nutrients in relation to the density of bacteria.

The respiratory tract provides nutrients for microbial growth at lower concentrations than the gastrointestinal tract and, accordingly, supports much lower bacterial densities [ 63 ]. The precise number of S. In addition, nasal mucus contains large amounts of macromolecular mucin glycoproteins. Mucins are covered with abundant and complex oligosaccharide structures [ 68 ], at least some of which can also serve as a carbon source for S.

While other species of bacteria thrive in the nose, too, and may compete for nutrients, S. For the S. Various mechanisms may contribute to the death of S. Mucociliary clearance, however, is the predominant force for the removal of bacteria and other particles from the nasal cavity [ 17 ]. Mucus effectively binds and transports bacteria, including S. While adherence to the epithelium is needed to sustain colonization [ 14 , 16 ], only a small portion of the bacterial population may be adherent, and when adherent cells divide, daughter cells move into the mucus layer.

We found that generation times of S. Growth during colonization increases bacterial density and facilitates transmission to another host [ 63 ]. Staphylococcal growth will also enhance resistance to colonization by competitors, ensuring that all available receptors remain occupied and nutrients get consumed.

Continuous growth may even be required to replenish the adherent population, since the epithelium is also shed, albeit at a lower rate than the mucus [ 14 ]. The balance between bacterial growth and removal likely will affect respiratory health. It is well documented that S. In contrast, little is known currently about growth rates of S. Limited oxygen availability in viscous sputum and continuous antibiotic treatment during chronic infection were suspected major growth constraints [ 51 ].

Generally, decreased staphylococcal growth rates during chronic infections are thought to hamper successful antibiotic treatment [ 71 ]. In contrast, acute infections with S.

In a mouse sepsis model, staphylococcal invasion was characterized by severe bottlenecks in the bacterial population due to the innate immune response, which were then followed by massive clonal expansions, with up to ,fold increases of the number of S. Hence, the cell division rates which we determined for nasal colonization in most cases were higher than the fastest documented net rates during fulminant disease progression.

Even though nutrient concentrations in nasal mucus are considerably lower than in blood plasma or sputum [ 20 ], conditions in the nasal environment may still be more favorable for growth due to the rich oxygen supply.

Future measurements of in-vivo replication rates of S. We here report absolute generation times for a commensal bacterium during natural colonization of the human host. We provide two lines of genomic evidence which concordantly indicate that S. Our results document that S. We provide basic growth rate data that will inform mathematical modelling of the dynamic microbial ecology of the human upper respiratory tract, which eventually may enable the development of novel diagnostics to predict the occasional transition from symptom-free carriage to infectious disease [ 2 ].

Finally, our data suggest that the lifestyle of a bacterial pathogen may have a major impact on its rate of molecular evolution. Bacterial isolates used in this work are listed in Additional file 1 : Table S1. Each fluctuation assay was performed in duplicate. The expected number of rifampicin resistance-causing mutations per culture m was calculated using the maximum-likelihood estimator applying newton.

Rates of rifampicin resistance were calculated by dividing m by the average final cell number CFU, see above. Statistical comparisons were carried out by using the likelihood ratio test LRT. The number and types of distinct mutations causing rifampicin resistance was determined by PCR amplification and Sanger-sequencing of rpoB gene fragments from independent, rifampicin-resistant S. Oligonucleotide primers are listed in Additional file 6 : Table S4. Experiments and analyses were performed in the same way for S.

Mutation accumulation experiments were carried out as described previously [ 41 ]. Briefly, for each of two S. Lines from strain 04— were passaged 58 times and lines from strain HO were passaged 77 times, and then colonies from each line were subjected to Illumina genome sequencing. To estimate the number of generations that had passed to form bacterial colonies, we enumerated the number of S.

Confidence intervals were calculated from a Poisson distribution by using the R function poisson. An overnight-culture of S. Nasal swab samples were collected anonymously from 48 adult volunteers by self-swabbing their anterior nares using dry, sterile Purflock swabs MWE Medical Wire, UK.

Participants confirmed they were not taking any antibiotic medication. Genomic DNA from S. PCR primers targeted the staphylococcal gyrase B gene [ 75 ] and the human interferon beta-1 gene Additional file 6 : Table S4. DNA from S. Briefly, Samtools v0.

DNA sequencing reads from nasal swab samples and from the growth experiment with S. To test for the effect of the reference sequence applied, sequencing reads were also mapped to genome sequences from S.

Peak-to-through ratios PTR of the sequencing coverage along the S. A polynomial regression of 2nd order was used to predict doubling times from nasal swab PTR values. The best model fit of PTR values to doubling times from the S. A polynomial fit of 2nd order yielded the lowest corrected Akaike information criterion value AICc, Morever, the polynomial fit of 2nd order yielded the largest adjusted R 2 value 0.

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People who often visit healthcare facilities and nursing home residents are also at an increased risk. Treatment depends on the type of infection caused by the bacteria.