Novel biallelic TRNT1 mutations lead to atypical SIFD and multiple immune defects

Mutations in the gene encoding transfer RNA(tRNA)nucleotidyltransferase,CCAadding 1(TRNT1),an enzyme essential for the synthesis of the 30-terminal CCA sequence in tRNA molecules,are associated with a rare syndrome of congenital sideroblastic anemia,B cell immunodeficiency,periodic fevers,and developmental delay(SIFD).Clinical manifestations and immunological phenotypes were assessed in a Chinese patient with novel compound heterozygous mutations in TRNT1.The patient required multiple hospitalizations starting at the age of 2 years for recurrent fevers without an infective cause.During the febrile episode,the patient was found to have microcytic hypochromic anemia,B cell lymphopenia,and hypogammaglobulinemia.Targeted gene sequencing identified novel compound heterozygous mutations in the TRNT1 gene(c.525delT,p.Leu176X;c.938T>C,p.Leu313Ser).Immunophenotyping revealed increased CD8^+T cells,CD4^+ terminally differentiated effector memory helper T lymphocytes(CD4 TEMRA),and CD4^+ effector memory lymphocytes(CD4 EM).Analysis of CD4^+T subsets identified decreased T follicular helper cells(Tfh)with a biased phenotype to Th2-like cells.The patient also showed a lower percentage of switched memory B(smB)cells.Additionally,defects in the cytotoxicity of the patient’s NK andγτT cells were shown by CD107alpha expression.In conclusion,TRNT1 mutations may lead to multiple immune abnormality especially humoral and cytotoxicity defects,which indicate that SIFD is not only suffered‘Predominantly antibody deficiencies’in IUIS classification system,and further studies are needed to understand the pathogenesis of immunodeficiency in these patients.

Single-nucleus transcriptomic profiling of multiple organs in a rhesus macaque model of SARS-CoV-2 infection

Infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple organs.However, cellular and molecular understanding of SARS-CoV-2 infection-associated pathology and immune defense features in different organs remains incomplete. Here, we profiled approximately 77 000single-nucleus transcriptomes of the lung, liver,kidney, and cerebral cortex in rhesus macaques(Macaca mulatta) infected with SARS-CoV-2 and healthy controls. Integrated analysis of the multiorgan dataset suggested that the liver harbored the strongest global transcriptional alterations. We observed prominent impairment in lung epithelial cells, especially in AT2 and ciliated cells, and evident signs of fibrosis in fibroblasts. These lung injury characteristics are similar to those reported in patients with coronavirus disease 2019(COVID-19).Furthermore, we found suppressed MHC class I/II molecular activity in the lung, inflammatory response in the liver, and activation of the kynurenine pathway,which induced the development of an immunosuppressive microenvironment. Analysis of the kidney dataset highlighted tropism of tubule cells to SARS-CoV-2, and we found membranous nephropathy(an autoimmune disease) caused by podocyte dysregulation. In addition, we identified the pathological states of astrocytes and oligodendrocytes in the cerebral cortex, providing molecular insights into COVID-19-related neurological implications. Overall, our multi-organ single-nucleus transcriptomic survey of SARS-CoV-2-infected rhesus macaques broadens our understanding of disease features and antiviral immune defects caused by SARS-CoV-2 infection,which may facilitate the development of therapeutic interventions for COVID-19.