3D Ex vivo tissue platforms to investigate the early phases of influenza a virus- and SARS-CoV-2-induced respiratory diseases

Abstract

Pandemic outbreaks of viruses such as influenza virus or SARS-CoV-2 are associated with high morbidity and mortality and thus pose a massive threat to global health and economics. Physiologically relevant models are needed to study the viral life cycle, describe the pathophysiological consequences of viral infection, and explore possible drug targets and treatment options. While simple cell culture-based models do not reflect the tissue environment and systemic responses, animal models are linked with huge direct and indirect costs and ethical questions. Ex vivo platforms based on tissue explants have been introduced as suitable platforms to bridge the gap between cell culture and animal models. We established a murine lung tissue explant platform for two respiratory viruses, influenza A virus (IAV) and SARS-CoV-2. We observed efficient viral replication, associated with the release of inflammatory cytokines and the induction of an antiviral interferon response, comparable to ex vivo infection in human lung explants. Endolysosomal entry could be confirmed as a potential host target for pharmacological intervention, and the potential repurposing potentials of fluoxetine and interferons for host-directed therapy previously seen in vitro could be recapitulated in the ex vivo model.

Cholesterol and COVID-19—therapeutic opportunities at the host/virus interface during cell entry

“…Antidepressants including fluoxetine revealed reduced SARS-CoV-2 infection in Vero-E6 and Calu-3a cells and a decline in viral titers in murine lung tissue 3D ex vivo explants, which is supported by several retrospective and observational studies for fluoxetine and hydroxyzine over the course of COVID-19 (Schloer et al, 2021;Schloer et al, 2022). Strikingly, the combination of itraconazole or fluoxetine with remdesivir, a nucleotide analogue that inhibits the SARS-CoV-2 RNA polymerase, displayed stronger antiviral activities compared to monotherapy, indicating that targeting multiple regulatory pathways may be a valuable therapeutic strategy (Schloer et al, 2020a).…”

25-hydroxycholesterol: an integrator of antiviral ability and signaling

“…Repurposing of antifungal drugs including itraconazole and posaconazole was found to play effective roles in restricting IAV, Ebola virus and SFV (Semliki Forest virus) by regulating cholesterol homeostasis ( 125 – 127 ). Besides, the antidepressant drug fluoxetine targeting acid sphingomyelinase exerts antiviral effects on SARS-CoV-2 and Ebola virus by inducing impaired endosomal acidification and sequestered cholesterol within endosomes ( 127 – 129 ). Statins, the broadly applied cholesterol-lowering drugs also serve as potent antiviral agents against different stages of virus cycle ( 130 ).…”

Short-term ex vivo tissue culture models help study human lung infectionsA review

“…Besides, the use of susceptible animal models is also limited because it may lead to problems such as high cost, moral and ethical controversies. [ 42 ]…”

“…Besides, the use of susceptible animal models is also limited because it may lead to problems such as high cost, moral and ethical controversies. [42] An ex vivo human lung culture model has been used to study the mechanisms of SARS-CoV-2 infection. [43][44][45] The research showed that SARS-CoV-2 replicated in human lung tissues very efficiently within a 48-hour interval.…”