Sex hormones, such as estrogen and testosterone, are steroid compounds with well-characterized effects on the coordination and development of vertebrate reproductive systems. Since their discovery, however, it has become clear that these “sex hormones” also regulate/influence a broad range of biological functions. In this review, we will summarize some current findings on how estrogens interact with and regulate inflammation and immunity. Specifically, we will focus on describing the mechanisms by which estrogens alter immune pathway activation, the impact of these changes during infection and the development of long-term immunity, and how different types of estrogens and their respective concentrations mediate these outcomes.

Influenza viruses infect approximately 20% of the global population annually, resulting in hundreds of thousands of deaths. While there are Food and Drug Administration (FDA) approved antiviral drugs for combating the disease, vaccination remains the best strategy for preventing infection. Due to the rapid mutation rate of influenza viruses, vaccine formulations need to be updated every year to provide adequate protection. In recent years, a great amount of effort has been focused on the development of a universal vaccine capable of eliciting broadly protective immunity. While universal influenza vaccines clearly have the best potential to provide long-lasting protection against influenza viruses, the timeline for their development, as well as the true universality of protection they afford, remains uncertain. In an attempt to reduce influenza disease burden while universal vaccines are developed and tested, many groups are working on a variety of strategies to improve the efficacy of the standard seasonal vaccine. This review will highlight the different techniques and technologies that have been, or are being, developed to improve the seasonal vaccination efforts against influenza viruses.

Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral replication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphorylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.

GPER1 in utero to the rescue!: Several common pathogens, including influenza A virus (IAV), can activate systemic type I interferon (IFN) signaling during pregnancy. Such infections would be expected to cause birth defects and fetal mortality, but maternal IAV infections rarely produce such effects, suggesting the presence of a protective mechanism in fetal tissues. Harding et al. used a CRISPR screen to uncover IFN regulators that can mediate differential IFN control across tissues in human cell lines. They found that G protein–coupled estrogen receptor 1 (GPER1), which is expressed in fetal tissues, acts as a protective suppressor of IFN responses in the placenta during maternal infection. In a mouse model, pharmacological activation of GPER1 shielded fetuses from maternal inflammation. Activation of GPER1 might be promising therapeutically to protect the fetus from both maternal and fetal infections. Science , this issue p. 271

The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS’ interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates the recruitment of caspase-8 and cFLIP_L to the MAVS signalosome and the subsequent cleavage of Ripk1 that terminates MAVS signaling. Consistently, mice with myeloid deficiency of protein geranylgeranylation showed improved survival upon influenza A virus infection. Our work revealed a critical role of protein geranylgeranylation in regulating antiviral innate immune response.

Flaviviruses are present on every continent and cause significant morbidity and mortality. In many instances, severe cases of infection with flaviviruses involve the invasion of and damage to the central nervous system (CNS). Currently, there are several mechanisms by which it has been hypothesized flaviviruses reach the brain, including the disruption of the blood–brain barrier (BBB) which acts as a first line of defense by blocking the entry of many pathogens into the brain, passing through the BBB without disruption, as well as travelling into the CNS through axonal transport from peripheral nerves. After flaviviruses have entered the CNS, they cause different neurological symptoms, leading to years of neurological sequelae or even death. Similar to neuroinvasion, there are several identified mechanisms of neuropathology, including direct cell lysis, blockage of the cell cycle, indication of apoptosis, as well as immune induced pathologies. In this review, we aim to summarize the current knowledge in the field of mechanisms of both neuroinvasion and neuropathogenesis during infection with a variety of flaviviruses and examine the potential contributions and timing of each discussed pathway.