Genomic surveillance reveals dynamic shifts in the connectivity of COVID-19 epidemics.

The maturation of genomic surveillance in the past decade has enabled tracking of the emergence and spread of epidemics at an unprecedented level. During the COVID-19 pandemic, for example, genomic data revealed that local epidemics varied considerably in the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage importation and persistence, likely due to a combination of COVID-19 restrictions and changing connectivity. Here, we show that local COVID-19 epidemics are driven by regional transmission, including across international boundaries, but can become increasingly connected to distant locations following the relaxation of public health interventions. By integrating genomic, mobility, and epidemiological data, we find abundant transmission occurring between both adjacent and distant locations, supported by dynamic mobility patterns. We find that changing connectivity significantly influences local COVID-19 incidence. Our findings demonstrate a complex meaning of "local" when investigating connected epidemics and emphasize the importance of collaborative interventions for pandemic prevention and mitigation.

Divergent Mast Cell Responses Modulate Antiviral Immunity During Influenza Virus Infection.

Influenza A virus (IAV) is a respiratory pathogen that infects millions of people each year. Both seasonal and pandemic strains of IAV are capable of causing severe respiratory disease with a high risk of respiratory failure and opportunistic secondary infection. A strong inflammatory cytokine response is a hallmark of severe IAV infection. The widespread tissue damage and edema in the lung during severe influenza is largely attributed to an overexuberant production of inflammatory cytokines and cell killing by resident and infiltrating leukocytes. Mast cells (MCs) are a sentinel hematopoietic cell type situated at mucosal sites, including the lung. Poised to react immediately upon detecting infection, MCs produce a vast array of immune modulating molecules, including inflammatory cytokines, chemokines, and proteases. As such, MCs have been implicated as a source of the immunopathology observed in severe influenza. However, a growing body of evidence indicates that MCs play an essential role not only in inducing an inflammatory response but in suppressing inflammation as well. MC-derived immune suppressive cytokines are essential to the resolution of a number of viral infections and other immune insults. Absence of MCs prolongs infection, exacerbates tissue damage, and contributes to dissemination of the pathogen to other tissues. Production of cytokines such as IL-10 and IL-6 by MCs is essential for mitigating the inflammation and tissue damage caused by innate and adaptive immune cells alike. The two opposing functions of MCs-one pro-inflammatory and one anti-inflammatory-distinguish MCs as master regulators of immunity at the site of infection. Amongst the first cells to respond to infection or injury, MCs persist for the duration of the infection, modulating the recruitment, activation, and eventual suppression of other immune cells. In this review, we will discuss the immune modulatory roles of MCs over the course of viral infection and propose that the immune suppressive mediators produced by MCs are vital to minimizing immunopathology during influenza infection.

The E3 Ubiquitin Ligase SIAH1 Targets MyD88 for Proteasomal Degradation During Dengue Virus Infection.

The dengue virus presents a serious threat to human health globally and can cause severe, even life-threatening, illness. Dengue virus (DENV) is endemic on all continents except Antarctica, and it is estimated that more than 100 million people are infected each year. Herein, we further mine the data from a previously described screen for microRNAs (miRNAs) that block flavivirus replication. We use miR-424, a member of the miR-15/16 family, as a tool to further dissect the role of host cell proteins during DENV infection. We observed that miR-424 suppresses expression of the E3 ubiquitin ligase SIAH1, which is normally induced during dengue virus 2 (DENV2) infection through activation of the unfolded protein response (UPR). Specific siRNA-mediated knockdown of SIAH1 also results in inhibition of DENV replication, demonstrating that this target is at least partly responsible for the antiviral activity of miR-424. We further show that SIAH1 binds to and ubiquitinates the innate immune adaptor protein MyD88 and that the antiviral effect of SIAH1 knockdown is reduced in cells in which MyD88 has been deleted by CRISPR/Cas9 gene editing. Additionally, MyD88-dependent signaling, triggered either by DENV2 infection or the Toll-like receptor 7 (TLR7) ligand imiquimod, is increased in cells in which SIAH1 has been knocked down by miR-424 or a SIAH1-specific siRNA. These observations suggest an additional pathway by which DENV2 harnesses aspects of the UPR to dampen the host innate immune response and promote viral replication.