Frontiers in Cellular and Infection Microbiology最新文献

Borrelia burgdorferi exists in a complex enzootic life cycle requiring differential gene regulation. P66, a porin and adhesin, is upregulated and essential during mammalian infection, but is not produced or required within the tick vector. We sought to determine whether the porin function of P66 is essential for infection. Vancomycin treatment of B. burgdorferi cultures was used to screen for P66 porin function and found to generate spontaneous mutations in p66 (bb0603). Three novel, spontaneous, missense P66 mutants (G175V, T176M, and G584R) were re-created by site-directed mutagenesis in an infectious strain background and tested for infectivity in mice by ID₅₀ experiments. Two of the three mutants retained infectivity comparable to the isogenic control, suggesting that B. burgdorferi can tolerate alteration to P66 porin function during infection. The third mutant exhibited highly attenuated infectivity and produced low levels of P66 protein. Interestingly, four isolates that were recovered for p66 sequencing from mouse tissues revealed novel secondary point mutations in genomic p66. However, these secondary mutations did not rescue P66 porin function. New structural modeling of P66 is presented and consistent with these experimental results. This is the first work to assess the contribution of P66 porin function to B. burgdorferi pathogenesis.

Messenger RNA (mRNA) vaccines offer an adaptable and scalable platform for cancer immunotherapy, requiring optimal design to elicit a robust and targeted immune response. Recent advancements in bioinformatics and artificial intelligence (AI) have significantly enhanced the design, prediction, and optimization of mRNA vaccines. This paper reviews technologies that streamline mRNA vaccine development, from genomic sequencing to lipid nanoparticle (LNP) formulation. We discuss how accurate predictions of neoantigen structures guide the design of mRNA sequences that effectively target immune and cancer cells. Furthermore, we examine AI-driven approaches that optimize mRNA-LNP formulations, enhancing delivery and stability. These technological innovations not only improve vaccine design but also enhance pharmacokinetics and pharmacodynamics, offering promising avenues for personalized cancer immunotherapy.

Co-infection with human immunodeficiency virus (HIV) significantly increases the incidence of human papillomavirus (HPV) infection and HPV-related cancers among men who have sex with men (MSM). Conversely, HPV infection can also influence HIV acquisition rates. HIV-induced immune suppression may affect chromosomal stability, gene expression, protein function and other molecular components in MSM with HPV-related cancers. Additionally, HIV infection also alters cellular mechanisms by compromising immune responses and epithelial integrity. In this review, we reviewed the influence of HIV on specific HPV-related cancers in MSM, including oropharyngeal squamous cell carcinoma, penile cancer, and anal cancer. We integrated epidemiological data from the past five years and discussed diagnosis and treatment strategies. Overall, our review offers crucial insights into the underlying molecular and cellular mechanisms of these co-infection MSM patients. Our review aims to assist future research in developing effective treatment strategies for MSM with HIV/HPV co-infection.

Background: Epidemiological risk factors such as the demography of a place, environment, food, livestock, and companion animals are known sources of Klebsiella pneumoniae infection. Whole-genome sequencing (WGS) has become a powerful tool to complement traditional microbiological characterization of foodborne pathogens. Moreover, K. pneumoniae has several species complexes (KpSC) and is very difficult to differentiate using routine microbiological methods. The present study aims to investigate the prevalence of K. pneumoniae in fish available in the retail market using WGS.

Methods: Isolation of K. pneumoniae, identification of K. pneumoniae isolates, and determination of the minimum inhibitory concentration (MIC) were performed. Whole-genome sequencing of K. pneumoniae genomes and phylogenomic analysis were conducted for visual comparison of the genomes. Furthermore, genomes of non-human origin that were submitted from India to the NCBI database were downloaded and included in the comparative analysis.

Results: The findings showed that many antibiotic-resistant genes (ARGs) are prominent, including acrD, BaeR, cpxA, mdtB, mdtC, CRP, H-NS, KpnE, KpnF, KpnG, KpnH, acrA, acrB, marA, ramB, oqxA, oqxB, LptD, and emrR. Four fish-sourced isolates had different blaSHV resistance gene variants. The presence of ARGs for aminoglycosides [aac(3)-IId], fluoroquinolones (oqxA, oqxB), and fosfomycin (fosA5, fosA6) in these K. pneumoniae isolates from fish sources was found. One of the CIFT-K6 isolates had the uncommon serotype of K. pneumoniae O3b with the high-risk clone "ST37." The ST515 sequence type was present in two K. pneumoniae isolates (CIFT-K7 and CIFT-K8), but the O3b serotype and ST192 allele type were present in the CIFT-K10 isolate.

Conclusion: To the best of our knowledge, this research study represents the first Indian report of K. pneumoniae linked to fish, specifically the high-risk clone 'ST37' and two other STs, 515 and 192. The most common plasmid type detected in all four isolates was IncFIB, and 75% of the isolates were IncFII and IncHI1B. The prevalence of ARGs linked to efflux pump resistance mechanisms is highlighted by the analysis of genome sequence data.

SERINC5 (serine incorporator 5), a member of the serine incorporator family, has been identified as a retrovirus restriction factor that inhibits the fusion of virions with the plasma membrane, thus blocking the release of the viral core into target cells and subsequently attenuating viral infectivity. Several viruses, such as human immunodeficiency virus (HIV), murine leukemia virus (MLV), and equine infectious anemia virus (EIAV), have evolved mechanisms to antagonize the host protein SERINC5 through HIV Nef, MLV glycosylated Gag, and the EIAV S2 protein. These viral proteins degrade SERINC5 on the cell surface through the endolysosomal system. In addition to its direct antiviral ability, SERINC5 also modulates immunity to inhibit the replication of retroviruses and nonretroviruses. This review summarizes the interaction between SERINC5 and viral replication, providing a promising avenue for fighting viral diseases.

Conserved histone methyltransferases of the DOT1 family are involved in replication regulation, cell cycle progression, stage differentiation, and gene regulation in trypanosomatids. However, the specific functions of these enzymes depend on the host evasion strategies of the parasites. In this study, we investigated the role of DOT1B in Leishmania mexicana, focusing on life cycle progression and infectivity. In contrast to Trypanosoma brucei, in which DOT1B is essential for the differentiation of mammal-infective bloodstream forms to insect procyclic forms, L. mexicana DOT1B (LmxDOT1B) is not critical for the differentiation of promastigotes to amastigotes in vitro. Additionally, there are no significant differences in the ability to infect or differentiate in macrophages or sand fly vectors between the LmxDOT1B-depleted and control strains. These findings highlight the divergence of the function of DOT1B in these related parasites, suggesting genus-specific adaptations in the use of histone modifications for life cycle progression and host adaptation processes.

Opportunistic pathogens are a major threat to people, especially those with impaired immune systems. Two of the most important microbes in this category are the fungus Candida albicans and Gram-positive bacteria of the genus Enterococcus, which share overlapping niches in the oral cavity, gastrointestinal and urogenital tracts. The clinical importance of oral C. albicans biofilm and its interaction with the host under immunosuppressive conditions remains largely understudied. Here, we used a mouse model of oropharyngeal candidiasis (OPC) with cortisone acetate injection on alternate days and a continuous supply of C. albicans in drinking water for three days, resulting in immunosuppression. Results showed abundant growth of resident oral bacteria and a strong C. albicans biofilm on the tongue consisting of hyphae which damaged papillae, the epidermal layer, and invaded tongue tissue with the accumulation of inflammatory cells as demonstrated by Grocott's methenamine silver and hematoxylin and eosin staining, respectively. The dispersed microbes from the oral biofilm colonized the gastrointestinal (GI) tract and damaged its integrity, disseminating microbes to other organs. Although no visible damage was observed in the kidney and liver, except increased lipid vacuoles in the liver cells, C. albicans was found in the liver homogenate. Intriguingly, we found co-occurrence of Enterococcus faecalis in the tongue, liver, and stool of immunosuppressed control and C. albicans infected organs. Targeted 16S rRNA and ITS2 amplicon sequencing of microbes from the fecal samples of mice confirmed the above results in the stool samples and revealed an inverse correlation of beneficial microbes in the dysbiosis condition. Our study shows that mucosal-oral infection of C. albicans under immunosuppressed conditions causes tissue damage and invasion in local and distant organs; the invasion may be aided by the overgrowth of the resident endogenous Enterobacteriaceae and other members, including the opportunistic pathogen Enterococcus faecalis.

Background: To explore the genetic characteristics of the Mycobacterium abscessus complex (MABC) population in China, given its rising clinical importance among nontuberculous mycobacteria.

Methods: We conducted population genetic analyses on 360 MABC genomes from China, focusing on core genome multilocus sequence typing (cgMLST), pan-genome characterization, population genetics, and antimicrobial resistance gene profiling.

Results: Our analysis identified 273 M. abscessus subsp. abscessus (Mab_A) and 87 M. abscessus subsp. massiliense (Mab_M) isolates, uncovering 68 sequence types (STs), with ST5 being the most common. cgMLST classified 33.3% of isolates into six dominant circulating clones (DCCs) and 49.4% into 59 genomic clusters at a threshold of 25 different alleles, including 18 international clusters linking Chinese isolates with seven other countries. The MABC pan-genome is open, with Mab_A exhibiting greater accessory gene diversity and higher gene turnover compared to Mab_M. Mobile genetic elements (MGEs), such as prophages and genomic islands, were prevalent across all genomes. 139 to 151 virulence factors (VFs) were identified per genome, with distinct accessory VFs in Mab_A and Mab_M affecting immune modulation and metabolism. Resistance gene profiling revealed ubiquitous mtrA, RbpA, and bla _MAB, with Mab_A-specific erm(41) conferring resistance to macrolides and β-lactams. Common rrs and rrl gene mutations indicated widespread resistance to aminoglycosides and macrolides, while gyrA mutations suggested emerging fluoroquinolone resistance. An acquired erm(46) gene, likely obtained via phage-mediated horizontal gene transfer, was detected in one Mab_A strain.

Conclusion: This study provides key genetic insights into the dynamics of MABC in China. The widespread distribution of DCCs, high genomic clustering rates, open pan-genome, and distinct resistance patterns between Mab_A and Mab_M, along with MGEs, highlight the need for targeted surveillance and tailored therapies to address emerging challenges in MABC infections.

Background: Patients with vitamin D deficiency are susceptible to increased microbial infection and increased risk of mortality. However, whether vitamin D supplementation would improve their prognosis remains uncertain.

Methods: We conducted a retrospective cohort study using data from MIMIC-IV database, a publicly available database containing clinical information on patients admitted to the ICU at Beth Israel Deaconess Medical Center (BIDMC) from 2008 to 2019. Adult patients with sepsis were included in the analysis. The exposure factor was vitamin D supplementation during the ICU stay. The primary outcome was 28-day all-cause mortality. Both propensity score matching (PSM) and stepwise regression analyses were employed to adjust for potential confounders.

Results: A total of 20230 eligible patients were enrolled in the entire unmatched cohort, and 8710 patients were included in the matched cohort. In PSM analysis, the 28-day all-cause mortality rate was 14.04% (250/1780) in the vitamin D group and 22.31% (1546/6930) in the no vitamin D group. Vitamin D supplementation was associated with decreased 28-day all-cause mortality (HR, 0.56; 95% CI, 0.49-0.64; p < 0.001). Subgroup analyses showed consistent benefits regardless of the baseline vitamin D status (deficiency: HR, 0.70; 95% CI, 0.33-1.50; p = 0.36; insufficiency: HR, 0.10; 95% CI, 0.03-0.34; p < 0.001; sufficiency: HR, 0.33; 95% CI, 0.12-0.88; p = 0.03). Additionally, vitamin D supplementation was associated with decreased ICU mortality (OR, 0.37; 95% CI, 0.29-0.48; p < 0.001) and reduced in-hospital mortality (OR, 0.57; 95% CI, 0.48-0.68; p < 0.001). Sensitivity analysis using the unmatched cohort confirmed these findings (HR, 0.57; 95% CI, 0.43-0.76; p < 0.001).

Conclusions: Vitamin D supplementation may reduce mortality in critically ill patients with sepsis. However, further high-quality prospective studies are still needed to validate these findings.

Introduction: Cnestis ferruginea is used frequently in African traditional medicine for treating infectious diseases. Previous bioassay-guided purification has identified hydroquinone as the major bio-active compound in the aforementioned plant, responsible for its antibacterial activity against Staphylococcus aureus. While the phenol hydroquinone can be directly extracted from the plant, it may undergo (reversible) oxidation under mild conditions to yield benzoquinone, a compound with known antimicrobial activity against i.a. S. aureus.

Methods: We, examined whether hydroquinone or its oxidation product, benzoquinone, is the active compound against bacteria such as S. aureus. To achieve this we performed broth microdilution (planktonic) and biofilm activity tests against two different strains of S. aureus. The inhibitory concentrations (IC₅₀) of benzoquinone and hydroquinone under various circumstances were compared, assessing their stability, and examining their effectiveness against two strains of S. aureus (Rosenbach and USA 300) in both planktonic and biofilm environments.

Results: Benzoquinone demonstrated antibacterial activity against S. aureus Rosenbach and USA 300 with IC₅₀ of 6.90 ± 2.30 mM and 7.72 ± 2.73 mM, respectively, while the corresponding values for hydroquinone were 15.63 ± 2.62 mM and 19.21 ± 4.84 mM, respectively. However, when oxidation was prevented by the addition of antioxidants such as ascorbic acid or glutathione, hydroquinone lost its antibacterial property, while benzoquinone retained activity. Comparing conditions in which hydroquinone could convert into benzoquinone against conditions in which this conversion was inhibited, showed that hydroquinone alone did not inhibit bacterial growth of S. aureus, while benzoquinone alone did.

Discussion: These results prove that the oxidation product benzoquinone is responsible for the antimicrobial activity previously ascribed to hydroquinone.