Researchers at the University of Amsterdam have conducted a study showing that heparan sulfate proteoglycans are important co-receptors that severe acute respiratory syndrome 2 (SARS-CoV-2) requires to infect host cells.
“Although angiotensin-converting enzyme 2 (ACE2) is the primary receptor for SARS-CoV-2, we identified heparan sulfate proteoglycans expressed by epithelial cells, alveolar macrophages and dendritic cells as co-receptors for SARS-CoV-2,” write Teunis Geijtenbeek (University of Amsterdam) and colleagues.
Furthermore, the study showed that low molecular weight heparin (LMWH) could block the heparan sulfate-mediated binding of SARS-CoV-2 to host epithelial cells and stop the virus from being disseminated by dendritic cells.
Given that LMWH inhalation is already considered safe as prophylactic therapy for COPD and asthma, the authors say the findings support the use of LMWH for both the prevention and early treatment of SARS-CoV-2.
“These results have imperative implications for our understanding of SARS-CoV-2 host cell entry and reveal an important target for novel prophylactic intervention,” writes the team.
A pre-print version of the paper is available in the server bioRxiv*, while the article undergoes peer review.
The COVID-19 pandemic
Since the first cases of coronavirus disease 2019 (COVID-19) were first identified in Wuhan, China, late last year, the causative agent – SARS-CoV-2 – has swept the globe and now infected approximately 22.2 million people and caused more than 783,000 deaths.
Disease outcomes range from mild respiratory illness to fatal conditions such as severe viral pneumonia, multi-organ disease, and respiratory failure.
SARS-CoV-2 is mainly transmitted via airborne droplets expelled through coughing or sneezing that subsequently infect mucosal surfaces in the nose, mouth, and eyes. The virus infects epithelial cells in the respiratory tract, gastrointestinal tract, and various other bodily tissues.
To date, there are no treatments available that can prevent infection, and in the absence of a vaccine, lockdown strategies and social distancing measures have been the only options for mitigating the spread of the virus. However, these approaches are not feasible in the long-term due to the associated negative socioeconomic impacts.
ACE2 and heparan sulfate may both be required for viral infection
The primary receptor SARS-CoV-2 uses to bind host cells is ACE2, an integral membrane protein that is highly expressed in epithelial cells lining the respiratory tract, ileum, esophagus, and liver.
SARS-CoV-2 virus binding to ACE2 receptors on a human cell, the initial stage of COVID-19 infection. Image Credit: Kateryna Kon / Shutterstock
However, Geijtenbeek and colleagues say it remains unclear whether SARS-CoV-2 also requires other receptors to access host cells and that recently it has been suggested that the virus interacts with heparan sulfate molecules and heparin.
What did the researchers do?
Now, the team has conducted a study that strongly suggests the heparan sulfate proteoglycans (HSPGs) Syndecan 1 and 4 are required for the virus to bind to and infect epithelial cells.
Viral binding to these HSPGs facilitates interaction with ACE2 and thereby subsequent infection, say the researchers.
The study also showed that primary subsets of dendritic cells attach to the HSPGs to facilitate ACE-2- independent viral dissemination. Dendritic cell subsets isolated from skin or from blood firmly bound the virus using HSPG and then disseminated it to target epithelial cells.
“These findings are important to develop prophylactics against SARS-CoV-2 or prevent dissemination early after infection,” writes the team.
Heparin treatments blocked infection
The researchers found that administering LMWH directly prevented SARS-CoV-2 from binding to and infecting epithelial cells and stopped dissemination by dendritic cells. Unfractionated heparin (UH) also efficiently inhibited SARS-CoV-2 infection and dissemination.
Geijtenbeek and colleagues report that both LMWH and UF abrogated infection to a similar degree as antibodies against ACE2, suggesting that both receptors are required for efficient virus infection.
“It further suggests that neutralizing antibodies isolated from COVID 19 patients could at least partially inhibit SARS-CoV-2 binding to heparan sulfate proteoglycans and thereby interfere with infection,” says the team.
The findings have important implications
The researchers say the findings have crucial implications in terms of understanding SARS-CoV-2 host cell entry and revealing an important target for new prophylactic approaches.
“LMWH inhalation has been studied to attenuate inflammatory responses in COPD and asthma patients and is considered safe to use as a prophylactic,” say Geijtenbeek and colleagues.
“The clinical use of LMWH to treat COVID-19 and our finding that LMWH block virus infection and dissemination strongly advocate for the prophylactic use of LMWH in individuals at risk for infection, or shortly after infection or even for a general population during outbreaks we still observe daily to limit transmission events quickly,” they conclude.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.