Emerging infectious diseases present great risks to public health. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), has become an urgent public health issue of global concern. It is speculated that the virus first emerged through a zoonotic spillover. Basic research studies have suggested that bats are likely the ancestral reservoir host. Nonetheless, the evolutionary history and host susceptibility of SARS-CoV-2 remains unclear as a multitude of animals has been proposed as potential intermediate or dead-end hosts. SARS-CoV-2 has been isolated from domestic animals, both companion and livestock, as well as in captive wildlife that were in close contact with human COVID-19 cases. Currently, domestic mink is the only known animal that is susceptible to a natural infection, develop severe illness, and can also transmit SARS-CoV-2 to other minks and humans. To improve foundational knowledge of SARS-CoV-2, we are conducting a synthesis review of its host diversity and transmission pathways. To mitigate this COVID-19 pandemic, we strongly advocate for a systems-oriented scientific approach that comprehensively evaluates the transmission of SARS-CoV-2 at the human and animal interface.

The emergence, spread, and persistence of antimicrobial resistance (AMR) remains a pressing global concern. Increased promotion of commercial small-scale agriculture within low-resource settings has facilitated an increased use in antimicrobials as growth promoters globally, creating antimicrobial-resistant animal reservoirs. We conducted a longitudinal field study in rural Ecuador to monitor the AMR of Escherichia coli populations from backyard chickens and children at three sample periods with approximately 2-month intervals (February, April, and June 2017). We assessed AMR to 12 antibiotics using generalized linear mixed effects models (GLMM). We also sampled and assessed AMR to the same 12 antibiotics in one-day-old broiler chickens purchased from local venders. One-day-old broiler chickens showed lower AMR at sample period 1 compared to sample period 2 (for 9 of the 12 antibiotics tested); increases in AMR between sample periods 2 and 3 were minimal. Two months prior to the first sample period (December 2016) there was no broiler farming activity due to a regional collapse followed by a peak in annual farming in February 2017. Between sample periods 1 and 2, we observed significant increases in AMR to 6 of the 12 antibiotics in children and to 4 of the 12 antibiotics in backyard chickens. These findings suggest that the recent increase in farming, and the observed increase of AMR in the one-day old broilers, may have caused the increase in AMR in backyard chickens and children. Small-scale farming dynamics could play an important role in the spread of AMR in low- and middle-income countries.

The development of engineered T cells to treat acute myeloid leukemia (AML) is challenging due to difficulty in target selection and the need for robust T-cell expansion and persistence. We designed a T cell stimulated to kill AML cells based on recognition of the AML-associated surface marker CLEC12A, via secretion of a CLEC12AxCD3 bispecific "engager" molecule (CLEC12A-ENG). CLEC12A-ENG T cells are specifically activated by CLEC12A, are not toxic to hematopoietic progenitor cells, and exhibit antigen-dependent AML killing. Next, we coupled stimulation of T-cell survival to triggering of a chimeric IL7 receptor with an ectodomain that binds a second AML-associated surface antigen, CD123. The resulting T cells, identified as CLEC12A-ENG.CD123IL7Ra T cells, demonstrate improved activation upon dual target recognition, kill AML, and exhibit antitumor activity in xenograft models. Enhanced T-cell activation conferred by CD123.IL7Ra was dependent both on recognition of the CD123 target and on IL7Ra-mediated downstream signaling. Expression of a chimeric IL7R targeted to a second tumor-associated antigen (TAA) should improve T-cell activity not only against hematologic malignancies, but perhaps against all cancers.

Oncolytic herpes simplex virus (oHSV) is a therapeutic modality that has seen substantial success for the treatment of cancer, though much remains to be improved. Commonly attenuated through the deletion or alteration of the γ134.5 neurovirulence gene, the basis for the success of oHSV relies in part on the malignant silencing of cellular pathways critical for limiting these viruses in healthy host tissue. However, only recently have the molecular mechanisms underlying the success of these treatments begun to emerge. Further clarification of these mechanisms can strengthen rational design approaches to develop the next generation of oHSV. Herein, we review our current understanding of the molecular basis for tumor susceptibility to γ134.5-attenuated oHSV, with particular focus on the malignant suppression of nucleic acid sensing, along with strategies meant to improve the clinical efficacy of these therapeutic viruses.

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Herpes simplex virus (HSV) infection relies on immediate early proteins that initiate viral replication. Among them, ICP0 is known, for many years, to facilitate the onset of viral gene expression and reactivation from latency. However, how ICP0 itself is regulated remains elusive. Through genetic analyses, we identify that the viral γ134.5 protein, an HSV virulence factor, interacts with and prevents ICP0 from proteasomal degradation. Furthermore, we show that the host E3 ligase TRIM23, recently shown to restrict the replication of HSV-1 (and certain other viruses) by inducing autophagy, triggers the proteasomal degradation of ICP0 via K11- and K48-linked ubiquitination. Functional analyses reveal that the γ134.5 protein binds to and inactivates TRIM23 through blockade of K27-linked TRIM23 autoubiquitination. Deletion of γ134.5 or ICP0 in a recombinant HSV-1 impairs viral replication, whereas ablation of TRIM23 markedly rescues viral growth. Herein, we show that TRIM23, apart from its role in autophagy-mediated HSV-1 restriction, down-regulates ICP0, whereas viral γ134.5 functions to disable TRIM23. Together, these results demonstrate that posttranslational regulation of ICP0 by virus and host factors determines the outcome of HSV-1 infection.

Herpes simplex virus (HSV) has persisted within human populations due to its ability to establish both lytic and latent infection. Given this, human hosts have evolved numerous immune responses to protect against HSV infection. Critical in this defense against HSV, the host protein stimulator of interferon genes (STING) functions as a mediator of the antiviral response by inducing interferon (IFN) as well as IFN-stimulated genes. Emerging evidence suggests that during HSV infection, dsDNA derived from either the virus or the host itself ultimately activates STING signaling. While a complex regulatory circuit is in operation, HSV has evolved several mechanisms to neutralize the STING-mediated antiviral response. Within this review, we highlight recent progress involving HSV interactions with the STING pathway, with a focus on how STING influences HSV replication and pathogenesis.

<p>Supplementary Figures 1-7</p>