Author: Shuvasree SenGupta

Editors: Lisa Pinatti, Lihan Xie, and Whit Froehlich

 

Keeping our immune system functional is important to stay healthy in the time of the COVID-19 (coronavirus disease 2019) pandemic. However, the same immune system is behind some of the worst symptoms of COVID-19, which may seem paradoxical. Components of the immune system, when not regulated properly, can boomerang back and cause harm to our own cells. As such, scientists speculate that some of the fatal complications seen with COVID-19 are because of the aberrant activation of a member of the innate immune cell population, known as neutrophils.

Neutrophils in charge of vital defensive functions

Neutrophils are the most abundant white blood cells in our blood. Every day, our body produces billions of neutrophils which circulate in the blood on the lookout for foreign invaders, like viruses.  Just like first responders, neutrophils promptly arrive at the sites of tissue injury or infection. Such prompt arrival requires neutrophils to migrate in a “swarming motion” as they sense certain chemicals released at the sites of foreign invasion. Upon sensing the intruder, activated neutrophils use one or more of their highly specialized weaponry to handle the situation. For instance, they may directly eat up pathogens or dead cell debris before digesting them, or destroy an infectious agent by expelling pre-stored digestive enzymes and antimicrobial agents from their storage bags known as granules or by discharging toxic oxygen species. Neutrophils can also eliminate pathogens by spitting out their genetic material (DNA) as web-like structures known as neutrophil extracellular traps or NETs.  A number of antimicrobial agents such as protein-degrading neutrophil elastase or NE and toxin-producing enzyme myeloperoxidase or MPO are usually studded in this sticky web, which serves to trap and kill the pathogen. All these neutrophil defense techniques are designed to provide the body an upper hand in its combat against infections as fast as possible.

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Major defensive structures of neutrophils

However, such promptness of the immune response sometimes comes with a price. Due to their non-specific approach, activated neutrophils, if not restrained in time, go haywire. They promote inflammation by relentlessly launching a variety of chemicals, (enzymes, oxygen species, peptides) that backfire and worsen the problem rather than solving it. In fact, neutrophils have recently been recognized as rather a powerful culprit in various inflammatory conditions such as chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), asthma, cardiovascular disease, cystic fibrosis (CF), and autoimmune disease. More recent studies have indicated a potential role for neutrophils in COVID-19 associated pathologies.

Immunopathological events in COVID-19

The virus causing the COVID-19 pandemic is known as SARS-CoV-2 (Severe Acute Respiratory Syndrome -CoronaVirus -2). As the name suggests, severe ARDS is the most serious clinical manifestation of SARS-CoV-2 infection. A similar clinical syndrome is also associated with other respiratory coronaviruses, SARS-CoV and Middle East Respiratory Syndrome-CoV (MERS-CoV), which caused the SARS and MERS outbreaks, respectively.

Although a majority of COVID-19 patients recover from fever, cough, and other milder symptoms, a subset of them succumb to viral pneumonia. Virus-inflicted injuries to the lungs lead to ARDS, thick mucus accumulation, and respiratory failure. When SARS-CoV-2 is recognized by the immune system, it starts a chain reaction to eliminate the virus. Interestingly, it is not only the viral infection but also the immune responses of the infected patients that sometimes contribute to disease severity. Patients with severe COVID-19 often manifest “cytokine storm” where small immune proteins known as cytokines and chemokines are detected in an overwhelming level in the serum. Those proteins drive massive inflammatory damage to the lung as well as multi-organ failure. Another common complication in COVID-19 is abnormal blood clotting inside blood vessels, or thrombotic events. Such events can lead to organ failure not only in the lung but throughout the body. In addition, severely affected patients have a surge of neutrophils in the circulation. Given their involvement in a number of other inflammatory conditions, scientists are studying neutrophils more closely to understand their role in COVID-19 infections.

Recent findings on potential roles of neutrophils in COVID-19 pathologies

 Neutrophils are currently under scientific scrutiny for propagating severe inflammation and thrombosis in COVID-19. Scientists have already found that the degree of increase of neutrophil percentage in the blood correlates with the severity of COVID-19. Researchers also detected the presence of neutrophils in lung autopsies from deceased COVID-19 patients.

Here, at the University of Michigan, studies led by Jason S. Knight and Yogendra Kanthi investigated the association of NETs in COVID19 pathologies. Knight and Kanthi group found potential NET breakdown products including cell-free DNA and MPO bound to DNA in the serum from hospitalized COVID-19 patients. Both products were also associated with increased neutrophil count in the blood. Importantly, higher amounts of cell-free DNA were found in the serum of patients with severe illness, requiring mechanical ventilation, than of those with milder symptoms. In a preprint version, the same group also reported elevated NETs in the blood of COVID-19 patients with thrombotic events. These findings further reinforce the idea that neutrophils are actively involved in COVID-19 pathologies.

NETs have recently been linked to conditions like ARDS in influenza, mucus accumulation in patients with CF, and blood clot formation in thrombotic disorders. The presence of NETs at high levels in the blood may lead to damage in the lungs, heart or kidneys due to small blood vessel blockage triggered by intravascular NETs. Scientists are therefore speculating that the excessive neutrophil load and the associated NET release in severe COVID-19 infection also inflict serious damage to the lung. Further research into the biology of neutrophils in COVID-19 will help to develop therapeutic strategies that will check their damage without limiting their protective functions.

Therapeutic approach to target neutrophil driven damage in COVID-19

 Manipulating neutrophils to dial down an overzealous immune system is envisioned to reduce the mortality and need for ventilation of COVID-19. Many of the existing clinical trials in this area, seeking to treat conditions like COPD, ARDS, asthma, cardiovascular disease, and CF, involve strategies that block either neutrophil navigation machinery (e.g, targeting CXCR2, a receptor critical for neutrophil migration) or neutrophil-derived tissue damaging content (e.g, inhibiting protein-degrading neutrophil elastase or NE); or degrade extracellular DNA (e.g, disintegrating NETs). To fulfill the urgent need for drugs effective against COVID-19, similar approaches are currently being used by biopharmaceutical companies in collaboration with scientists in academia, who are involved with COVID-19 studies. Current clinical trials for COVID-19 therapies targeting neutrophils include testing DNA degrading enzyme DNase (Dornase Alfa) to destroy NETs, or small molecule inhibitor (Brensocatib) and peptide inhibitor (lonodelestat) to target NE activity.

As in other inflammatory conditions, neutrophils might not be the single component to drive COVID-19 immunopathologies. It is also worth noting that not all COVID-19 patients necessarily have significant neutrophil infiltration in the lung. Scientists, therefore, envision that monitoring the presence of neutrophils or their products in the blood and lung fluid from the patients will guide developing personalized targeted therapy against COVID-19. Hopefully, in the coming days, weeks, and months, more studies will advance our knowledge on the role of immune system in COVID-19 severities and that will be the key to guide therapies.

 


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Shuvasree SenGupta (Sree) received her PhD in Microbiology and Immunology from the University of Louisville. Sree then joined the lab of Dr. Carole Parent as a postdoctoral fellow at the University of Michigan. Sree’s current research focuses on exploring the role of neutrophils in breast cancer progression and metastasis. Sree is also the co-chair of Members in Transition and Training Focus Group (MTTG) of the Society for leukocyte Biology (SLB) where Sree is committed to help the junior trainee members (graduate students, postdocs, newly minted faculties) to provide a resourceful platform for their career development. In her free time, Sree likes listening to music, reading suspense novels, and sketching.

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