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Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne virus, prevalent in more than 30 countries worldwide. Human infection by this virus leads to severe illness, with an average case fatality of 40%. There is currently no approved vaccine or drug to treat the disease. Neutralizing antibodies are a promising approach to treat virus infectious diseases. This study generated 37 mouse-derived specific monoclonal antibodies against CCHFV Gc subunit. Neutralization assays using pseudotyped virus and authentic CCHFV identified Gc8, Gc13, and Gc35 as neutralizing antibodies. Among them, Gc13 had the highest neutralizing activity and binding affinity with CCHFV Gc. Consistently, Gc13, but not Gc8 or Gc35, showed in vivo protective efficacy (62.5% survival rate) against CCHFV infection in a lethal mouse infection model. Further characterization studies suggested that Gc8 and Gc13 may recognize a similar, linear epitope in domain II of CCHFV Gc, while Gc35 may recognize a different epitope in Gc. Cryo-electron microscopy of Gc-Fab complexes indicated that both Gc8 and Gc13 bind to the conserved fusion loop region and Gc13 had stronger interactions with sGc-trimers. This was supported by the ability of Gc13 to block CCHFV GP-mediated membrane fusion. Overall, this study provides new therapeutic strategies to treat CCHF and new insights into the interaction between antibodies with CCHFV Gc proteins. Author summary: Crimean-Congo hemorrhagic fever (CCHF) is a priority disease by the World Health Organization (WHO). It is a deadly viral infectious disease with case fatalities up to 40%, and no approved vaccine or treatment. Neutralizing antibodies are a promising approach toward treating viral infections, as exemplified in other hemorrhagic fevers such as Ebola. Currently, there are few reports of efficient neutralizing antibodies against CCHF virus (CCHFV). This study successfully screened mouse-derived monoclonal antibodies with high in vitro neutralizing activity and in vivo protective efficacy against CCHFV infection. Among those, mAb Gc13 was the most efficient because it strongly bound to the highly conserved fusion loop regions of the CCHFV Gc subunit, thus blocking the crucial virus membrane fusion process. This study highlights the potential of neutralizing antibody-based strategies for CCHF treatment. [ABSTRACT FROM AUTHOR]

Background: Vitamin D is related to human immunity, so we used Bayesian network model to analyze and infer the relationship between vitamin D level and the acid-fast bacilli (AFB) smear-positive after two months treatment among pulmonary tuberculosis (TB) patients. Methods: This is a cross-sectional study. 731 TB patients whose vitamin D level were detected and medical records were collected from December 2019 to December 2020 in XinJiang of China. Logistic regression was used to analyze the influencing factors of second AFB smear-positive. Bayesian network was used to further analyze the causal relationship among vitamin D level and the second AFB smear-positive. Results: Baseline AFB smear-positive (OR = 6.481, 95%CI: 1.604~26.184), combined cavity (OR = 3.204, 95%CI: 1.586~6.472), full supervision (OR = 8.173, 95%CI:1.536~43.492) and full management (OR = 6.231, 95%CI:1.031~37.636) were not only the risk factors and can also be considered as the reasons for second AFB smear-positive in TB patients (Ensemnle > 0.5). There was no causal relationship between vitamin D level and second AFB smear-positive (Ensemnle = 0.0709). Conclusions: The risk factors of second AFB smear-positive were baseline AFB smear-positive, combined cavity, full supervision and full management. The vitamin D level in TB patients was not considered as one of the reasons for the AFB smear-positive. [ABSTRACT FROM AUTHOR]

Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is well known to play a critical function in cancer, autoimmune and neurodegenerative diseases. However, its role in host-pathogen interactions has not been characterized yet. Herein, we identified that kynurenine-3-monooxygenase (KMO), a key rate-limiting enzyme in the KP, and quinolinic acid (QUIN), a key enzymatic product of KMO enzyme, exerted a novel antiviral function against a broad range of viruses. Mechanistically, QUIN induced the production of type I interferon (IFN-I) via activating the N-methyl-d-aspartate receptor (NMDAR) and Ca2+ influx to activate Calcium/calmodulin-dependent protein kinase II (CaMKII)/interferon regulatory factor 3 (IRF3). Importantly, QUIN treatment effectively inhibited viral infections and alleviated disease progression in mice. Furthermore, kmo-/- mice were vulnerable to pathogenic viral challenge with severe clinical symptoms. Collectively, our results demonstrated that KMO and its enzymatic product QUIN were potential therapeutics against emerging pathogenic viruses. Author summary: The outbreaks of emerging infectious diseases have become a severe challenge worldwide, and therefore it is a public health priority to explore novel broad-spectrum antiviral agents with various mechanisms. This study reported that kynurenine-3-monooxygenase (KMO), a key rate-limiting enzyme during tryptophan metabolism, showed promise as a novel broad-spectrum antiviral factor against emerging pathogenic viruses. We further found that quinolinic acid (QUIN), an enzymatic product of KMO, could also act as a novel broad-spectrum antiviral agent. We then systematically studied the underlying mechanisms and broadly antiviral function of KMO and QUIN in vitro and in vivo. Our data highlight the importance of exploring novel antiviral targets from the key enzymes and their metabolites in tryptophan metabolism. [ABSTRACT FROM AUTHOR]

Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is well known to play a critical function in cancer, autoimmune and neurodegenerative diseases. However, its role in host-pathogen interactions has not been characterized yet. Herein, we identified that kynurenine-3-monooxygenase (KMO), a key rate-limiting enzyme in the KP, and quinolinic acid (QUIN), a key enzymatic product of KMO enzyme, exerted a novel antiviral function against a broad range of viruses. Mechanistically, QUIN induced the production of type I interferon (IFN-I) via activating the N-methyl-d-aspartate receptor (NMDAR) and Ca2+ influx to activate Calcium/calmodulin-dependent protein kinase II (CaMKII)/interferon regulatory factor 3 (IRF3). Importantly, QUIN treatment effectively inhibited viral infections and alleviated disease progression in mice. Furthermore, kmo-/- mice were vulnerable to pathogenic viral challenge with severe clinical symptoms. Collectively, our results demonstrated that KMO and its enzymatic product QUIN were potential therapeutics against emerging pathogenic viruses., Competing Interests: The authors have declared that no competing interests exist.