Articles of Significant Interest in This Issue

doi:10.1128/JVI.00205-21

DOI: 10.1128/JVI.00205-21

An Atypical Giant Virus Expressing Genes for Energy Metabolism

Viruses have long been viewed as entities relying on the host cell machinery to propagate. Blanc-Mathieu et al. (e02446-20) describe a novel giant alga-infecting virus with a unique structure, an atypical infection profile, and an unprecedented number of genes involved in energy metabolism (such as the tricarboxylic acid [TCA] cycle and the β-oxidation pathway). One of these genes (the succinate dehydrogenase subunit A gene) is transcribed during infection. Moreover, homologs of this gene seem to be widely present in viral genomes of the Tara Oceans data set. This discovery provides evidence that viruses which are able to directly modulate the energy metabolism of their hosts by using their own genetic repertoire are widespread in the global ocean.

Cryo-electron tomogram of the PkV RF01 virion.

Enhanced Zika Virus Virulence during Direct Transmission Chains in Mice

Zika virus (ZIKV) is unique among arboviruses in its capacity to bypass the mosquito vector and be transmitted directly human to human, eliminating the evolutionary constraint of host alternation. Riemersma et al. (e02218-20) report substantial increases in ZIKV fitness and virulence in mice after serial mouse passage, but not after serial mosquito or alternating passage. Deep sequencing revealed the consistent emergence of four amino acid substitutions during serial mouse passage, but rarely observed during serial mosquito or alternating passage, including a previously described virulence-enhancing mutation. These findings suggest that direct human transmission chains could enable the emergence of more virulent ZIKV strains.

Four amino acid substitutions consistently emerged during serial passage of Zika virus in mice.

Th2 Cytokine Modulates Herpesvirus Reactivation in a Cell Type-Specific Manner

Murine gammaherpesvirus 68 (MHV68) establishes chronic infections and only reactivates to produce infectious virus when precise signals are received, such as the parasite-induced cytokine IL-4. It is unknown if the same signals can reactivate MHV68 in all infected cell types. Wang et al. (e01946-20) found that expression of IL-4 receptor on macrophages, but not B cells, was required for efficient MHV68 reactivation from latency in vivo upon administration of IL-4 complexes plus anti-interferon gamma (anti-IFN-γ) blocking antibody. These findings indicate that regulation of herpesvirus latency and reactivation is cell type specific. Understanding of reactivation signal requirements may lead to therapies against gammaherpesvirus reactivation.

MHV68 reactivation from peritoneal macrophages upon IL-4c/anti-IFN-γ treatment.

Insights into SARS-CoV-2 Sensing and (Lack of) Impact of the Interferon Response in Lung Cells

Recognition of pathogens by intracellular immune sensors induces an interferon response, which generally helps in controlling viral replication. Rebendenne et al. (e02415-20) report a high production of interferons induced by melanoma differentiation-associated protein 5 (MDA-5)-mediated sensing of SARS-CoV-2 in lung epithelial cells. However, these cells are unable to control viral replication, whereas similar doses of interferon prevent replication when added prior to infection, in particular in primary human lung cells. These findings pinpoint the ambiguous interplay between the interferon response and SARS-CoV-2 replication, the understanding of which is essential to guide future therapeutic interventions.

Airyscan microscopy of primary lung cells infected by SARS-CoV-2.

Instability, a Novel Property of the Influenza A Virus Host Shutoff Factor PA-X

PA-X, a recently discovered influenza A virus protein, reduces host immune responses to infection, but is paradoxically protective for the host in many strain backgrounds because it reduces immunopathology. PA-Xs from different strains vary in sequence, but how these differences alter PA-X biology and activity is unknown. Levene et al. (e02312-20) show that PA-X proteins from multiple influenza virus strains are markedly unstable, with considerable strain differences in turnover rates. They link strain-dependent differences in stability to specific differences in PA-X protein sequence. This work begins unraveling a novel regulatory mechanism of PA-X that may impact its host shutoff activity during infection.