Tomato brown rugose fruit virus (ToBRFV) has had major impacts on tomato production worldwide since its emergence in ~2014. The most critical factor behind the global pandemic of ToBRFV is the escape of the long-standing tomato tobamovirus resistance gene, Tm-22. ToBRFV has spurred research and brought renewed interest to genetic mechanisms of resistance against tobamoviruses for use in commercial tomato breeding. Many new potential sources of resistance to ToBRFV have been reported in peer-reviewed publications and commercial patents. However, the identity of genes responsible for resistance traits remains mostly elusive, and breeding these traits from wild relatives into commercial elite tomato varieties has negatively impacted tomato production by affecting fruit quality and development. Tm-1 has been the focus of multiple publications investigating the molecular basis in preventing ToBRFV replication, often linked to unknown resistance genes on other chromosomes. The role of Tm-1 includes complex genetic interactions, expression and gene dosage effects, gene duplications, orthologous variants, and particularly resistance escape mechanisms which can all affect the strength of Tm-1-mediated resistance. Other novel resistance traits are also increasingly vulnerable to resistance-breaking isolates. Here, we review recent major developments relating to ToBRFV resistance and breeding of commercial varieties.
Objective: To evaluate the efficacy and safety of umifenovir for the treatment and prophylaxis of influenza and other acute respiratory viral infections (ARVIs), including evidence from Russian-language clinical trials not previously incorporated into international systematic reviews. Methods: PubMed, eLibrary, China National Knowledge Infrastructure, and national archives were searched for randomized controlled trials (RCTs) and prospective or retrospective studies comparing umifenovir with placebo, no antiviral therapy, or oseltamivir. Results: Twenty-three studies were included: 12 therapeutic (n = 5083) and 11 prophylactic (n = 13,663). In RCT subgroups, umifenovir reduced intoxication symptoms (MD: −0.94 days; 95% CI: −1.62 to −0.26) and overall illness duration (MD: −1.17 days; 95% CI: −2.23 to −0.10) but not fever duration (MD: −0.58 days; 95% CI: −1.31 to 0.16). In the overall analysis, umifenovir reduced the risk of complications (RR: 0.39; 95% CI: 0.24–0.62). Prophylaxis reduced laboratory-confirmed influenza (RR: 0.39; 95% CI: 0.28–0.54). Adverse events were infrequent 3.6% (95% CI: 2.4–4.8%) and did not differ significantly from placebo (RR 0.59; 95% CI: 0.34–1.03). Conclusions: Umifenovir was associated with improved clinical outcomes and reduced infection risk, with a favorable safety profile. Inclusion of regionally published evidence expands the available evidence base.
Progressive enrichment of agalactosylated IgG G0 glycoforms has been repeatedly associated with severe and fatal COVID-19. Similar hypogalactosylated IgG phenotypes have also been described in persistent viral infection, post-infectious immune-mediated disease, and autoimmunity, suggesting that these conditions converge on a broader pathological immune response pattern. Evidence from autoimmune and inflammatory conditions indicates that persistent inflammatory signaling can remodel B-cell and germinal-center glycosylation pathways, thereby reducing IgG Fc galactosylation. Despite the substantial literature documenting these changes across different pathological conditions, the upstream processes that initiate and sustain progressive G0 enrichment remain largely unresolved, and no unifying upstream mechanism has been established across these conditions. We suggest that xenosialylation may represent one upstream amplification mechanism. Exogenous N-glycolylneuraminic acid (Neu5Gc) can be incorporated into human glycoconjugates, while humans possess heterogeneous anti-Neu5Gc repertoires. During intense antiviral antibody production, Neu5Gc-bearing IgG could be recognized by pre-existing and/or evolving anti-Neu5Gc responses, promoting immune-complex formation, clearance, and inflammatory amplification. The model predicts a temporal sequence linking Neu5Gc-bearing antigen-specific IgG, anti-Neu5Gc repertoire engagement, xenoimmune inflammation, and subsequent G0 enrichment, providing a directly testable mechanistic framework.
Interferon-stimulated genes (ISGs) mount an antiviral defense by targeting both viral components and cellular pathways required for infection. Here, we show that the interferon- and virus-inducible antiviral factor TRIM69 suppresses cellular AMP-activated protein kinase (AMPK) signaling and restricts replication of both RNA and DNA viruses. Ectopic expression of TRIM69 inhibited Sendai virus (SeV)-induced autophagy and suppressed phosphorylation of AMPK and its downstream target, ULK1, in response to viral infection and nutrient deprivation. Consistent with inhibition of this proviral AMPK signaling pathway, TRIM69 expression strongly restricted replication of paramyxoviruses and pneumoviruses, including SeV, respiratory syncytial virus (RSV), human parainfluenza virus type 3 (HPIV3), and herpesviruses, e.g., herpes simplex virus type 1 (HSV-1). Consistent with these findings, knockdown of endogenous TRIM69 enhanced viral replication, demonstrating a physiological antiviral role for TRIM69. In addition to suppressing viral replication, TRIM69 supported the expression of antiviral genes, including IFNB1, IFIT2, and IFIT3, suggesting amplification of the innate antiviral signaling. Together, these findings identify TRIM69 as a broad antiviral ISG that targets the cellular AMPK pathway and contributes to host innate immune responses against viruses.
The T-antigens (T-ags) encoded by Polyomaviruses (PyV) have multiple roles during viral DNA replication. There is still, however, considerable uncertainty regarding the functions of T-ag during different stages of DNA replication and the regulation of this process. As examples, how cell cycle dependent phosphorylation of a single threonine residue regulates PyV DNA replication has not been established, the purpose of the N-terminal J-domain during DNA replication in vivo is not understood and it is not clear how p53 is displaced from the surface of T-ag. The failure to resolve these issues is due, in part, to previous structural studies utilizing individual domains of T-ag rather than full-length T-ag molecules. Therefore, we have used AlphaFold3 to model the structure of full-length SV40 T-ag in the presence of a model DNA replication fork, co-factors, and phosphorylation of Thr 124. These modeling studies indicate that cell-cycle dependent phosphorylation of T-ag residue Thr 124 stabilizes a conformation in which the J-domain is located over the helicase domain. In this position, J-domain residues form multiple bonds with helicase domain residues that form the binding site for p53. Therefore, it is proposed that the SV40 J-domain (along with hsc70) has a role in the displacement of p53 from the surface of T-ag, a process that may enable the recruitment of the polymerase ⍺-primase complex and the subsequent initiation of viral DNA replication.
