PLoS Pathogens最新文献

Rare genes in bacterial pangenomes have historically been considered non-essential, dispensable, or even costly, and largely excluded from in-depth analyses due to their perceived redundancy, high variability, and presumed neutral evolutionary origin. However, whether rare genes contribute to metabolic robustness when core genes are lost remains an open question. In this study, we systematically investigate the role of rare metabolic genes in Escherichia coli, revealing their essentiality in maintaining metabolic functions under core gene loss. Through a pangenome-scale reconstruction of 15311 strain-specific genome-scale models (panGEM) and over 22.4 million gene knockout simulations, we demonstrate that: (i) 9.4% of rare metabolic genes are essential in at least one of three key host environments-feces, serum, and urine; (ii) 41% of strains rely on at least one rare essential metabolic gene for survival; (iii) rare metabolic genes emerge as a result of microniche adaptation, and (iv) panGEM allows for the prediction of a subset of highly conserved metabolic reactions with minimal genetic diversity as stable drug targets. These findings challenge the common view that rare genes primarily serve as evolutionary byproducts of genome fluidity and reveal their critical role in metabolic resilience.

Interferon-stimulated genes (ISGs) play a pivotal role in the innate immune response to viral infection. Among them, SAMD9 and its paralog SAMD9L have recently emerged as important antiviral effectors with translation-inhibitory activity. While both proteins restrict poxvirus, rotavirus and reovirus replication, only SAMD9L has been shown to inhibit HIV and other lentiviruses. In this study, we identify human SAMD9L as a potent and broad-spectrum restriction factor that targets multiple medically relevant flaviviruses, including West Nile virus (WNV), Zika virus (ZIKV), dengue virus (DENV), and Usutu virus (USUV). Exogenous expression of SAMD9L, but not SAMD9, efficiently suppressed replication of all tested flaviviruses. Furthermore, its knockdown in human myeloid cells, including microglial cells and primary macrophages, impaired the antiviral activity of type I interferon, identifying SAMD9L as a key antiviral ISG in primary target cells of flavivirus infection. Mechanistically, we demonstrate that SAMD9L inhibits viral replication by targeting the translation of flaviviral RNA, and that this activity depends on its Schlafen-like ribonuclease domain, previously implicated in the inhibition of HIV-1 translation. Interestingly, although SAMD9 does not inhibit flavivirus replication, it is able to repress the translation of flaviviral RNA outside the context of infection, suggesting that its activation may be virus-specific or that flaviviruses have evolved mechanisms to evade or counteract SAMD9's antiviral activity. Finally, we confirm that SAMD9 and SAMD9L overexpression induces activation of the innate immune response. However, this immunostimulatory function is dispensable for SAMD9L-mediated antiviral activity, since SAMD9L is able to restrict flavivirus replication independently of innate immune activation. Together, our findings broaden the known antiviral repertoire of SAMD9L, establish its essential role in restricting flavivirus replication via translational repression, and highlight its function as a key component of the cellular defenses against flaviviruses in myeloid cells.

Natural competence is one of the mechanisms of horizontal gene transfer, an important process that contributes to host-use evolution and other types of environmental adaptation in bacteria. Recently, the plant pathogen Xylella fastidiosa has undergone expansion of its host and geographic ranges. Natural competence has been empirically documented for a few strains of X. fastidiosa, but its prevalence across genotypes and populations is largely unknown. In this study, we characterized the natural competence in vitro of 142 X. fastidiosa strains from diverse hosts and geographic origins, and revealed substantial variability among strains, particularly across subspecies. X. fastidiosa subsp. fastidiosa strains were largely naturally competent, while only 15% of studied subsp. multiplex strains showed recombination, and none of the strains classified in other subspecies were competent. While recombination rates in vitro were associated with subspecies classification, host and climatic variables from the area of isolation did not explain differences in recombination across strains. A genome-wide association study identified several genes linked to variation in natural competence, including a heretofore unknown role for xadA2, which codes for a surface afimbrial adhesin, and the already known fimbrial adhesin type IV pili genes pilY1-1 and pilY1-3. Overall, this study highlights the variability of natural competence among X. fastidiosa strains, that could have an impact on their potential for adaptation to the environment.

The rapid evolution of SARS-CoV-2 and the subsequent emergence of Omicron subvariants pose significant challenges to the efficacy of existing vaccines and therapeutics, including those previously reported most broad neutralizing antibodies (bnAbs). Here, we investigated the molecular basis of the altered neutralization profile of a bnAb, 1C4, against recent variants. 1C4 is effective against early variants from Alpha to Omicron BQ.1, but is circumvented by BQ.1.1, XBB and thereafter variants, primarily due to an additional R346T mutation that diminishes its binding affinity. Cryo-electron microscopy analysis revealed that despite the loss of neutralizing potency, 1C4 retained residual binding to the spike protein of immune-evasive variants such as XBB, which harbor altered receptor-binding domain (RBD). Furthermore, 1C4 exhibited a diminished capacity to inhibit ACE2 engagement with Omicron variants, amplifying the intricacies of viral immune evasion tactics. To address this, we employed the mi3-SpyCatcher-based nanoparticle to polymerize 1C4 (mi3-1C4), which reestablished the neutralization potency against recent variants by enhancing avidity via multivalent binding. Such multivalent binding can promote efficient spike aggregation as well as viral cross-linking, thereby providing enhanced protection against both the infection of Beta and XBB variants in a hamster model. Together, our findings delineate the molecular landscape of immune evasion by neutralizing antibodies and provide strategic insight for the adaptation of antibody engineering to keep pace with viral evolution.

[This corrects the article DOI: 10.1371/journal.ppat.1013166.].

Redundancy in biology is, at a glance, counterintuitive because if the function of two gene products completely overlaps then, throughout the course of evolution, one of the genes will likely accumulate mutations to the point of loss-of-function. The consensus is that partial functional overlap, for example, divergent secondary functions, play a major role in redundancy conservation. This asymmetrical nature offers a crucial advantage: phenotypic plasticity, which ensures that an essential cellular function can adapt to changes in the environment. In this context, the human pathogen Mycobacterium tuberculosis is an interesting example. Despite being an obligate pathogen that has been co-evolving with the human host for millennia, M. tuberculosis genome retains redundant functions at multiple levels that allow the bacilli to adapt to extremely heterogeneous environments in the human host. This review explores how M. tuberculosis functional redundancies mirror the heterogeneity of both intra- and extracellular host niches, with a focus on energy metabolism. Finally, we discuss the challenges and opportunities of functional redundancies in the context of drug development.

Older adults have decreased vaccine efficacy, but the adjuvanted recombinant VZV-gE zoster vaccine (RZV) is highly efficacious. We investigated memory-like innate immune responses after RZV and after the zoster vaccine live (ZVL), which is much less efficacious. RZV increased NK, monocyte, and DC activation in response to in vitro VZV-gE stimulation for up to 5 years post-vaccination, while ZVL increased only DC responses to VZV for up to 90 days. In purified monocyte and NK cell cocultures, RZV recipients showed increased responses to VZV-gE, HCMV and HSV antigenic stimulation post-vaccination. ATAC-seq analysis of purified monocytes revealed decreased accessibility in areas of the TGFβ1 gene. scRNA-seq and immunoproteomics confirmed decreased TGFβ1 transcription and translation, respectively. Exogenous supplementation and inhibition of TGFβ1 modulated in vitro monocyte responses to VZV-gE. In conclusion, RZV generated homologous (VZV-gE) and heterologous (HCMV, HSV) trained immunity in monocytes through genomic repression of the regulatory cytokine TGFβ-1. Cytokine modulation may represent a novel mechanism of generating trained immunity in myeloid cells.

Coronaviruses express a repertoire of accessory proteins for evading host immune responses. A small internal (I) accessory gene overlaps with the nucleocapsid (N) gene in an alternative reading frame of viruses that belong to the genus Betacoronavirus. Previous studies reported that I proteins of SARS-CoV (9b), MERS-CoV (8b) and SARS-CoV-2 (9b) inhibit type I interferon (IFN-I) expression through distinct mechanisms and have different roles in pathogenesis. In contrast, the functions of the I proteins of human coronaviruses HCoV-HKU1 (7b) and HCoV-OC43 (8b) have not been previously reported. Although HCoV-HKU1 and HCoV-OC43 predominantly cause common cold in healthy adults (common cold CoVs, CCCoVs), susceptible individuals infected with these viruses can develop severe disease. The lack of robust reverse genetic systems, tissue culture and animal models limit the study of HCoV-HKU1 and HCoV-OC43 pathogenesis. Here, we examined how the heterologous expression of the HCoV-HKU1 and HCoV-OC43 I proteins impact pathogenesis in a mouse model of infection using a prototypic betacoronavirus. We inserted the I gene of HCoV-HKU1 (ORF 7b) and HCoV-OC43 (ORF 8b) independently into the genome of a neurotropic strain of mouse hepatitis virus (J2.2). J2.2 infection is well characterized with clearly defined immune responses which allows the study of these genes in the context of authentic coronavirus infection. We showed that ORF 7b of HCoV-HKU1, but not ORF 8b of HCoV-OC43, ameliorated MHV-J2.2 pathogenesis while ORF 8b of MERS-CoV exacerbated disease. The presence of HCoV-HKU1 ORF 7b decreased virus titers and cytokine expression while ORF 8b of MERS-CoV led to increased immune cell infiltration and virus titers in mice after J2.2 infection. Moreover, proteins expressed by ORF 7b of HCoV-HKU1 and ORF 8b of HCoV-OC43 showed different patterns of subcellular localization. Overall, our findings suggest that the I genes of different betacoronaviruses play unique roles in pathogenesis.