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In rare cases, hepatitis A virus (HAV) and hepatitis B virus (HBV) can cause fulminant viral hepatitis (FVH), characterized by massive hepatocyte necrosis and an inflammatory infiltrate. Other viral etiologies of FVH are rarer. FVH is life-threatening, but the patients are typically otherwise healthy, and normally resistant to other microbes. Only a small minority of infected individuals develop FVH, and this is the key issue to be addressed for this disease. In mice, mouse hepatitis virus 3 (MHV3) infection is the main model for dissecting FVH pathogenesis. Susceptibility to MHV3 differs between genetic backgrounds, with high and low mortality in C57BL6 and A/J mice, respectively. FVH pathogenesis in mice is related to uncontrolled inflammation and fibrinogen deposition. In humans, FVH is typically sporadic, but rare familial forms also exist, suggesting that there may be causal monogenic inborn errors. A recent study reported a single-gene inborn error of human immunity underlying FVH. A patient with autosomal recessive complete IL-18BP deficiency was shown to have FVH following HAV infection. The mechanism probably involves enhanced IL-18- and IFN-gamma-dependent killing of hepatocytes by NK and CD8 T cytotoxic cells. Proof-of-principle that FVH can be genetic is important clinically, for the affected patients and their families, and immunologically, for the study of immunity to viruses in the liver. Moreover, the FVH-causing IL18BP genotype suggests that excessive IL-18 immunity may be a general mechanism underlying FVH, perhaps through the enhancement of IFN-gamma immunity.

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

Humans homozygous or hemizygous for variants predicted to cause a loss of function (LoF) of the corresponding protein do not necessarily present with overt clinical phenotypes. We report here 190 autosomal genes with 207 predicted LoF variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups. No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as LoF. Of the 179 remaining variants in 166 genes, only 11 alleles in 11 genes had previously been confirmed experimentally to be LoF. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes). The 41 dispensable olfactory receptor genes displayed a relaxation of selective constraints similar to that observed for other olfactory receptor genes. The 125 dispensable nonolfactory receptor genes also displayed a relaxation of selective constraints consistent with greater redundancy. Sixty-two of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Of the 179 LoF variants, 68 could be tested for two neutrality statistics, and 8 displayed robust signals of positive selection. These latter variants included a known FUT2 variant that confers resistance to intestinal viruses, and an APOL3 variant involved in resistance to parasitic infections. Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted LoF alleles reveals both redundancies and advantages of such deficiencies for human survival.

Identifying the native range of invasive species is useful to understand their evolution and natural history, as well as to develop new methods to control potentially harmful introduced organisms. The clonal raider ant,Ooceraea biroi, is an introduced species and an increasingly important social insect model organism, but its native range remains unknown. Here, we report a new series ofO. biroicollections from Bangladesh, Singapore, Vietnam and China. We use a molecular phylogeny constructed with five gene fragments from 27 samples to determine that invasive lineages ofO. biroioriginated in Bangladesh. These lineages may have spread from Bangladesh via the historically significant Bay of Bengal shipping ports.Ooceraea biroishares multiple features of its biology with other introduced ants, including parthenogenesis, retention of heterozygosity and presence of multiple egg-layers in the colony. Using laboratory rearing and microsatellite markers, we show that colonies collected from disturbed habitat in Bangladesh have these traits in common with colonies from the invasive range. Ancestral populations with sexual reproduction in primary habitats either remain to be discovered or have gone extinct. Our findings advance our understanding of the global spread of the clonal raider ant and highlight a suite of general traits that make certain ants prone to becoming invasive.

The IgG Fc domain has the capacity to interact with diverse types of receptors, including the neonatal Fc receptor (FcRn) and Fc gamma receptors (Fc gamma Rs), which confer pleiotropic biological activities. Whereas FcRn regulates IgG epithelial transport and recycling, Fc effector activities, such as antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis, are mediated by Fc gamma Rs, which upon cross-linking transduce signals that modulate the function of effector leukocytes. Despite the well-defined and nonoverlapping functional properties of FcRn and Fc gamma Rs, recent studies have suggested that Fc ?Rs mediate transplacental IgG transport, as certain Fc glycoforms were reported to be enriched in fetal circulation. To determine the contribution of Fc gamma Rs and FcRn to the maternal-fetal transport of IgG, we characterized the IgG Fc glycosylation in paired maternal-fetal samples from patient cohorts from Uganda and Nicaragua. No differences in IgG1 Fc glycan profiles and minimal differences in IgG2 Fc glycans were noted, whereas the presence or absence of galactose on the Fc glycan of IgG1 did not alter Fc gamma RIIIa or FcRn bind-ing, half-life, or their ability to deplete target cells in Fc gamma R/FcRn humanized mice. Modeling maternal-fetal transport in Fc gamma/FcRn humanized mice confirmed that only FcRn contributed to trans-placental transport of IgG; IgG selectively enhanced for FcRn binding resulted in enhanced accumulation of maternal antibody in the fetus. In contrast, enhancing Fc gamma RIIIa binding did not result in en-hanced maternal-fetal transport. These results argue against a role for Fc gamma Rs in IgG transplacental transport, suggesting Fc engineering of maternally administered antibody to enhance only FcRn binding as a means to improve maternal-fetal transport of IgG.

Liver regeneration and metabolism are highly interconnected. Here, we show that hepatocyte-specific ablation of RNA polymerase II (Pol II)-associated Gdown1 leads to down-regulation of highly expressed genes involved in plasma protein synthesis and metabolism, a concomitant cell cycle re-entry associated with induction of cell cycle-related genes (including cyclin D1), and up-regulation of p21 through activation of p53 signaling. In the absence of p53, Gdown1-deficient hepatocytes show a severe dysregulation of cell cycle progression, with incomplete mitoses, and a premalignant-like transformation. Mechanistically, Gdown1 is associated with elongating Pol II on the highly expressed genes and its ablation leads to reduced Pol II recruitment to these genes, suggesting that Pol II redistribution may facilitate hepatocyte re-entry into the cell cycle. These results establish an important physiological function for a Pol II regulatory factor (Gdown1) in the maintenance of normal liver cell transcription through constraints on cell cycle re-entry of quiescent hepatocytes.

Dear Editor, The management of hidradenitis suppurativa (HS), a chronic inflammatory skin disease, deserves special consideration in the context of the Coronavirus 2019 (COVID‐19) pandemic. A new Global Hidradenitis Suppurativa COVID‐19 Registry has been developed to capture data on the risks, clinical course and outcomes of COVID‐19 in patients with HS. Caused by the virus SARS‐CoV‐2, COVID‐19 is an easily transmissible disease, which, in its most severe form, is characterized by respiratory failure and multiple organ dysfunction triggered by a cytokine storm response. It predominates in older adults and those with significant comorbidities.

Therapeutic interventions in colorectal cancer are dependent on immune responses to dying epithelial cells that are modulated by specific members of the gut microbiota.

Influenza viruses infect millions of people around the globe annually, usually causing self-limited upper respiratory tract infections. However, a small but non-negligible proportion of patients suffer from life-threatening pulmonary disease. Those affected include otherwise healthy individuals, and children with primary infections in particular. Much effort has been devoted to virological studies of influenza and vaccine development. By contrast, the enormous interindividual variability in susceptibility to influenza has received very little attention. One interesting hypothesis is that interindividual variability is driven largely by the genetic makeup of the infected patients. Unbiased genomic approaches have been used to search for genetic lesions in children with life-threatening pulmonary influenza. Four monogenic causes of severe influenza pneumonitis-deficiencies of GATA2, IRF7, IRF9, and TLR3-have provided evidence that severe influenza pneumonitis can be genetic and often in patients with no other severe infections. These deficiencies highlight the importance of human type I and III IFN-mediated immunity for host defense against influenza. Clinical penetrance is incomplete, and the underlying mechanisms are not yet understood. However, human genetic studies have clearly revealed that seemingly sporadic and isolated life-threatening influenza pneumonitis in otherwise healthy individuals can be genetic.