Mounting evidence has associated Zika virus (ZIKV) infection with congenital malformations, including microcephaly, which raises global alarm. Nonetheless, mechanisms by which ZIKV disrupts neurogenesis and causes microcephaly are far from being understood. In this study, we discovered direct effects of ZIKV on neural progenitor cell development by inducing caspase-1– and gasdermin D (GSDMD)-mediated pyroptotic cell death, linking ZIKV infection with the development of microcephaly. Importantly, caspase-1 depletion or its inhibitor VX-765 treatment reduced ZIKV-induced inflammatory responses and pyroptosis, and substantially attenuated neuropathology and brain atrophy in vivo. Collectively, our data identify caspase-1– and GSDMD-mediated pyroptosis in neural progenitor cells as a previously unrecognized mechanism for ZIKV-related pathological effects during neural development, and also provide treatment options for ZIKV-associated diseases.

The rapidly emerging human health crisis associated with the Zika virus (ZIKV) epidemic and its link to severe complications highlights the growing need to identify the mechanisms by which ZIKV accesses hosts. Interferon response protects host cells against viral infection, while the cellular factors that mediate this defense are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified, only a few have been characterized for their antiviral potential, target specificity and mechanisms of action. In this work, we focused our investigation on the possible antiviral effect of a novel ISG, C19orf66 in response to ZIKV infection and the associated mechanisms. We found that ZIKV infection could induce C19orf66 expression in ZIKV-permissive cells, and such an overexpression of C19orf66 remarkably suppressed ZIKV replication. Conversely, the depletion of C19orf66 led to a significant increase in viral replication. Furthermore, C19orf66 was found to interact and co-localize with ZIKV nonstructural protein 3 (NS3), thus inducing NS3 degradation via a lysosome-dependent pathway. Taken together, this study identified C19orf66 as a novel ISG that exerts antiviral effects against ZIKV by specifically degrading a viral nonstructural protein. These findings uncovered an intriguing mechanism of C19orf66 that targeting NS3 protein of ZIKV, providing clues for understanding the actions of innate immunity, and affording the possible availability of new drug targets that can be used for therapeutic intervention. "Guangdong Te Zhi program" youth science and technology talent of project (2015TQ01R281); Guangdong MEDP Fund Author summary ZIKV represents a serious threat to global health with particular relevance to microcephaly and other congenital abnormalities in newborns, and Guillain-Barré syndrome, meningoencephalitis, multi-organ failure in adults. Despite the global health threat of Zika virus infection, there is currently no vaccine or effective antiviral therapy available for the disease. As widely recognized, interferon signaling is key to establishing a strong antiviral state in host cells, mainly mediated through the anti-viral effects of numerous interferon-stimulated genes (ISGs). This work described our novel finding of the antiviral effect of a novel ISG, C19orf66, and its underlying mechanisms. We identified C19orf66 as a novel ISG that exerts antiviral effects against ZIKV by specifically interacting and colocalizing with the ZIKV nonstructural (NS) protein NS3, which inducing NS3 degradation via a lysosome-dependent pathway. Thus, this work broadens the understanding of the pivotal roles of C19orf66 in the interaction between the host and ZIKV, which might further provide a rational basis for developing novel anti-ZIKV strategies. PLOS NEGLECTED TROPICAL DISEASESC19orf66 suppresses ZIKV replication by target viral NS3 PLOS Neglected Tropical Diseases | https://doi.org/10.

Background: Animal experiments have shown the anticancer activity of Toxoplasma gondii (T. gondii), but its effect on the prognosis of cancer patients is unclear. Thus, the present study aimed to investigate the prognostic role of anti-T. gondii IgG in breast cancer patients and the modification effect of cytokines. Methods: A total of 1121 breast cancer patients were recruited between 2008 and 2018 and followed up until December 31, 2021. Anti-T. gondii IgG and cytokines were measured using an enzyme-linked immunosorbent assay (ELISA) kit and a multiplex assay platform. Endpoints were overall survival (OS) and progression-free survival (PFS). Survival and multiplicative interaction analyses were performed using multivariate Cox regression models. Results: According to the cutoff value of optical density (OD=0.111), 900 (80.29%) and 221 (19.71%) patients were divided into two groups: low or high anti-T. gondii IgG. Compared to patients with a low anti-T. gondii IgG level, the adjusted hazard ratios (HRs) of OS and PFS for patients with high anti-T. gondii IgG levels were 0.60 (95% confidence interval (CI): 0.37-0.99) and 0.67 (0.46-0.98), respectively. These associations were profound among patients with a high cytokine score (HR=0.29, 95% CI: 0.10-0.82 for OS; HR=0.30, 95% CI: 0.13-0.69 for PFS), accompanied by a significant interaction between the level of anti-T. gondii IgG and the cytokine score (P interaction =0.019 for PFS); interleukin-17 (IL-17) and interleukin-9 (IL-9) were the main contributors to the interaction. Conclusion: Anti-T. gondii IgG was found to be beneficial to breast cancer survival, especially in women with systematic inflammation and high IL-17 or IL-9 levels, suggesting the potential of T. gondii as a prognostic marker and a novel immunotherapy approach for cancer patients.

Background: Previous studies have found that acute febrile infection may decrease the risk of breast cancer. Meanwhile, it is well known that interleukin-6 (IL-6) played dual roles in the tumor microenvironment. Fever may stimulate IL-6 production, and IL-6 rs1800796 also influences the expression of IL-6. However, the impact of fever and its interaction with IL-6 rs1800796 on breast cancer survival remains to be explored. Methods: This was a prospective cohort study of 4223 breast cancer patients. Exposures were pre-/post-diagnostic infection-induced fever and rs1800796 polymorphism. The endpoints were overall survival (OS) and progression-free survival (PFS). Adjusted hazard ratios were obtained using multivariate Cox proportional hazards regression models. Results: Compared to women without pre-diagnostic fever, the adjusted HR of progression for those with pre-diagnostic fever was 0.81 (95%CI 0.66-0.99), particularly for CC genotype of IL-6 rs1800796 (HR 0.53; 95%CI 0.36-0.79). OS was also better (HR 0.59; 95%CI 0.36-0.99) among women with the CC genotype exposed to pre-diagnostic fever, accompanying with a significant interaction (P=0.021). Post-diagnostic fever conferred better PFS for breast cancer (HR 0.72; 95%CI 0.52-1.00). Irrespective of the genotype of IL-6, lymph node-positive women with post-diagnostic fever (HR 0.57; 95%CI 0.37-0.89) had a lower risk of progression than lymph node-negative women (HR 1.12; 95%CI 0.70-1.79). Conclusions: Infection-induced fever was beneficial to breast cancer survival, particularly for women who were CC genotype of IL-6 rs1800796 or node-positive. Impact: This study provides new insight into the roles of infection-induced fever as a potential prognostic marker and therapy regimen for breast cancer.

Background Reproductive tract infections influenced a series of inflammatory processes which involved in the development of breast cancer, while the processes were largely affected by estrogen. The present study aimed to explore the associations of breast cancer risk and prognosis with reproductive tract infections and the modification effects of estrogen exposure. Methods We collected history of reproductive tract infections, menstruation and reproduction from 1003 cases and 1107 controls and a cohort of 4264 breast cancer patients during 2008–2018 in Guangzhou, China. We used logistic regression model to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for risk; Cox model was applied to estimate the hazard ratios (HRs) and 95% CIs for progression-free survival (PFS) and overall survival (OS). Results It was found that previous reproductive tract infections were negatively associated with breast cancer risk (OR = 0.80, 95%CI, 0.65–0.98), particularly for patients with more menstrual cycles (OR = 0.74, 95%CI, 0.57–0.96). Patients with previous reproductive tract infections experienced better OS (HR = 0.61; 95% CI, 0.40–0.94) and PFS (HR = 0.84; 95% CI, 0.65–1.09). This protective effect on PFS was only found in patients with more menstrual cycles (HR = 0.52, 95% CI:0.34–0.79, Pinteraction = 0.015). Conclusions The findings suggested that reproductive tract infections may be protective for the initiation and development of breast cancer, particularly for women with a longer interval of lifetime estrogen exposure.