Functional characterisation of the ACE2 orthologues in Drosophila provides insights into the neuromuscular complications of COVID-19, 2023, Cauchi

Functional characterisation of the ACE2 orthologues in Drosophila provides insights into the neuromuscular complications of COVID-19

Highlights

• A large percentage of patients with COVID-19 have neuromuscular manifestations.
• Loss of Drosophila ACE2 orthologues Ance or Ance3 impaired motoric ability.
• Ance or Ance3 knockdown induced unique and overlapping transcriptional changes.
• Genes with a synaptic function were particularly vulnerable to splicing alterations.
• Findings favour ACE2 interference as a cause of COVID-19 neuromuscular disturbances.
  

Abstract
SARS-CoV-2, the virus responsible for the coronavirus disease of 2019 (COVID-19), gains cellular entry via interaction with the angiotensin-converting enzyme 2 (ACE2) receptor of host cells. Although SARS-CoV-2 mainly targets the respiratory system, the neuromuscular system also appears to be affected in a large percentage of patients with acute or chronic COVID-19.

The cause of the well-described neuromuscular manifestations resulting from SARS-CoV-2 infection remains unresolved. These may result from the neuromuscular-invasive capacity of the virus leading to direct injury. Alternatively, they may be the consequence of ACE2 inactivation either due to viral infection, ACE2 autoantibodies or both. Here, we made use of the Drosophila model to investigate whether ACE2 downregulation is sufficient to induce neuromuscular phenotypes.

We show that moderate gene silencing of ACE2orthologues Ance or Ance3 diminished survival on exposure to thermal stress only upon induction of neuromuscular fatigue driven by increased physical activity. A strong knockdown of Ance or Ance3 directed to muscle reduced or abolished adult viability and caused obvious motoric deficits including reduced locomotion and impaired flight capacity. Selective knockdown of Ance and Ance3 in neurons caused wing defects and an age-dependent decline in motor behaviour, respectively, in adult flies. Interestingly, RNA sequencingallowed us to discover several differentially spliced genes that are required for synaptic function downstream of Ance or Ance3 depletion.

Our findings are therefore supportive of the notion that loss of a RAS-independent function for ACE2 contributes to the neuromuscular manifestations associated with SARS-CoV-2 infection.


https://www.sciencedirect.com/science/article/abs/pii/S0925443923001849

A news report https://timesofmalta.com/articles/view/maltese-research-unlock-mystery-surrounding-longcovid.1049164