Graphical Abstract Highlights d SARS-CoV-2-infected ferrets exhibit elevated body temperature and virus replication d SARS-CoV-2 is shed in nasal washes, saliva, urine and feces d SARS-CoV-2 is effectively transmitted to naive ferrets by direct contact d SARS-CoV-2 infection leads acute bronchiolitis in infected ferrets

A highly pathogenic avian influenza virus, H5N1, caused disease outbreaks in poultry in China and seven other east Asian countries between late 2003 and early 2004; the same virus was fatal to humans in Thailand and Vietnam. Here we demonstrate a series of genetic reassortment events traceable to the precursor of the H5N1 viruses that caused the initial human outbreak in Hong Kong in 1997 (refs 2-4) and subsequent avian outbreaks in 2001 and 2002 (refs 5, 6). These events gave rise to a dominant H5N1 genotype (Z) in chickens and ducks that was responsible for the regional outbreak in 2003-04. Our findings indicate that domestic ducks in southern China had a central role in the generation and maintenance of this virus, and that wild birds may have contributed to the increasingly wide spread of the virus in Asia. Our results suggest that H5N1 viruses with pandemic potential have become endemic in the region and are not easily eradicable. These developments pose a threat to public and veterinary health in the region and potentially the world, and suggest that long-term control measures are required.

Highlights d Of several cytokines tested, only synergism of TNF-a and IFN-g induces PANoptosis d TNF-a and IFN-g-mediated PANoptosis perpetuates cytokine storm d TNF-a and IFN-g shock mirrors cytokine storm syndromes, including COVID-19 d Neutralizing TNF-a and IFN-g protects against SARS-CoV-2, HLH, and sepsis in mice

SUMMARY Virus-induced IL-1β and IL-18 production in macrophages is mediated via a caspase-1 pathway. Multiple microbial components, including viral RNA, are thought to trigger assembly of the cryopyrin inflammasome and consequent caspase-1 activation. Here we demonstrate that cryopyrin−/− and caspase-1−/− mice are more susceptible than wildtype controls following infection with a pathogenic influenza A virus. This profile of enhanced morbidity correlates with decreased neutrophil and monocyte recruitment and reduced cytokine and chemokine production. Despite the effect on innate immunity, cryopyrin-deficiency was not associated with any obvious defect in virus control or on the later emergence of the adaptive response. Early epithelial necrosis was, however, more severe in the infected mutants, with extensive collagen deposition leading to later respiratory compromise. These findings reveal a novel function of the cryopyrin inflammasome in healing responses. Cryopyrin and caspase-1 are clearly central to both innate immunity and to moderating lung pathology in influenza pneumonia.

Migration to intestinal mucosa putatively depends on local activation because gastrointestinal lymphoid tissue induces expression of intestinal homing molecules, whereas skin-draining lymph nodes do not. This paradigm is difficult to reconcile with reports of intestinal T cell responses after alternative routes of immunization. We reconcile this discrepancy by demonstrating that activation within spleen results in intermediate induction of homing potential to the intestinal mucosa. We further demonstrate that memory T cells within small intestine epithelium do not routinely recirculate with memory T cells in other tissues, and we provide evidence that homing is similarly dynamic in humans after subcutaneous live yellow fever vaccine immunization. These data explain why systemic immunization routes induce local cell-mediated immunity within the intestine and indicate that this tissue must be seeded with memory T cell precursors shortly after activation.