Biology subjects

Forrow, S.

Publications and source records attributed to Forrow, S..

3 recordsLinked to original sources

bioRxiv2024

A human-ACE2 knock-in mouse model for SARS-CoV-2 infection recapitulates respiratory disorders but avoids neurological disease associated with the transgenic K18-hACE2 model.

Animal models have been instrumental in elucidating the pathogenesis of SARS-CoV-2 infection and testing COVID-19 vaccines and therapeutics. Wild-type (WT) mice are not susceptible to many SARS-CoV-2 variants, therefore transgenic K18-hACE2 mice have emerged as a standard model system. However, this model is characterized by severe disease, particularly associated with neuroinfection, which leads to early humane endpoint euthanasia. Here, we established a novel knock-in (KI) mouse model by inserting the original K18-hACE2 transgene into the collagen COL1A1 locus using a recombinase mediated cassette exchange (RMCE) system. Once the Col1a1-K18-hACE2 mouse colony was established, animals were challenged with a B.1 SARS-CoV-2 (D614G) isolate and were monitored for up to 14 days. Col1a1-K18-hACE2 mice exhibited an initial weight loss similar to the K18-hACE2 transgenic model but did not develop evident neurologic clinical signs. The majority of Col1a1-K18-hACE2 mice did not reach the preestablished humane endpoint, showing progressive weight gain after 9 days post-infection (dpi). Importantly, despite this apparent milder pathogenicity of the virus in this mouse model compared to the K18-hACE2 transgenic model, high levels of viral RNA were detected in lungs, oropharyngeal swab, and nasal turbinate. Remaining lesions and inflammation in lungs were still observed after 14 dpi. In contrast, although low level viral RNA could be detected in a minority of Col1a1-K18- hACE2 animals, no brain lesions were observed at any timepoint. Overall, Col1a1-K18- hACE2 mice constitute a new model for investigating SARS-CoV-2 pathogenesis and treatments, with potential implications for studying long-term COVID-19 sequelae. ImportanceK18-hACE2 mice express high levels of the human protein ACE2, the receptor for SARS- CoV-2, and can therefore be infected by this virus. These animals have been crucial to understand viral pathogenesis and to test COVID-19 vaccines and antiviral drugs. However, K18-hACE2 often die after infection with initial SARS-CoV-2 variants likely due to a massive brain infection that does not occur in humans. Here, we used a technology known as knock-in that allows for the targeted insertion of a gene into a mouse and we have generated a new hACE2-mouse. We have characterized this new animal model demonstrating that the virus replicates in the respiratory tract, damaging lung tissue and causing inflammation. In contrast to K18-hACE2 mice, only limited or no brain infection could be detected, and most animals recovered from infection with remaining lung lesions. This new model could be instrumental for the study of specific disease aspects such as post-COVID condition, sequelae, and susceptibility to reinfection.

microbiology↗

bioRxiv2024

Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within Interleukin-6 family cytokines

Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in glandular epithelium of KrasG12D; Pik3caH1047R or Trp53R172H and/or ablation of Pten or Trp53. We find that KrasG12D;Pik3caH1047Ris sufficient to induce adenomas, and that lesions progress to carcinoma when also harboring Pten-deletions. Additional challenge with either Trp53 loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling in response to gp130 family cytokines remained as a gatekeeper for all stages of tumor development, metastatic progression required a mutant Trp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with poorer survival of patients with high IL6 expression, we identify IL6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer.

cancer biology↗

bioRxiv2022

Brain-keratinocyte communication suffices for epidermal daily homeostasis

In mammals, an integrated network of molecular oscillators drives daily rhythms of tissue-specific homeostatic processes. This circadian clock network is required for maintaining health and is compromised by disease and lifestyle choices, such as diet and exercise. However, critical properties of this systemic network, such as which tissues communicate to coordinate their respective programs of daily physiology, and the exact homeostatic processes requiring each communication pathway, remain undefined. To dissect daily inter-tissue communication, we have constructed in mice a minimal clock network comprising only two nodes: the peripheral epidermal clock and the central brain clock. By circadian transcriptomic and functional characterization of this isolated connection, we have identified a previously unknown gatekeeping function of the peripheral tissue clock with respect to systemic inputs. That is, the epidermal clock concurrently integrates and corrects brain signals to ensure timely execution of epidermal daily physiology. Specifying the integrative arm of the clock, we identify that timely cell cycle termination in the epidermal stem cell compartment is dependent upon incorporation of clock-driven signals originating from the brain. Unexpectedly, and in contrast, the epidermal clock corrects potentially disruptive feeding-related signals to ensure that DNA replication occurs at the optimum time of day. Together, we present a novel approach for cataloguing the systemic dependencies of a given tissue, and in turn identify an essential gate-keeping function of peripheral circadian clocks that guarantees tissue homeostasis.

cell biology↗