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"Inflammatory Tsunami" Causes Severe Disease After Infection with the SARS-CoV-2 Coronavirus

In This Article

  • SARS-CoV-2, the coronavirus that is causing the pandemic of COVID-19, is transmitted in both the symptomatic and asymptomatic stages of disease
  • The virus is transmitted via respiratory droplets following close unprotected contact and via fomites; airborne and fecal-oral transmission have not been verified
  • Acute respiratory distress syndrome, the primary cause of death, arises from a remarkably strong cytokine storm that develops rapidly and unpredictably; it can occur even in people who initially presented with mild to moderate symptoms
  • Little is known about the correlates of immunity in SARS-CoV-2 infection, which is slowing down the development of a vaccine

After infection with SARS-CoV-2, the coronavirus that's causing the pandemic of COVID-19, one of the first signs of severe disease is a remarkably strong cytokine storm—an "inflammatory tsunami," according to Galit Alter, PhD, principal investigator at the Ragon Institute of Massachusetts General Hospital, the Massachusetts Institute of Technology and Harvard University and Samana Cay MGH Research Scholar.

Dr. Alter described the pathogenesis of COVID-19 during a Medical Grand Rounds at Mass General on March 12, 2020, presented by members of the Greater Boston Consortium for Pathogen Readiness.

Transmission Dynamics

Dr. Alter explained that genetically, SARS-CoV-2 is 82% identical to SARS-CoV-1, which caused the severe acute respiratory syndrome (SARS) epidemic of 2002–2003. However, unlike its predecessor, SARS-CoV-2 is transmitted in both the symptomatic and asymptomatic stages of infection. Thus, the pace of SARS-CoV-2 transmission has been greatly accelerated by the international and domestic travel of individuals who don't yet know they are infected.

SARS-CoV-2 is transmitted via respiratory droplets following close unprotected contact and via fomites (objects that harbor pathogens, such as handrails). Airborne transmission has not been reported.

Potential Therapeutic Target

An intriguing finding is the presence of the SARS-CoV-2 receptor, ACE2, along the lung epithelium. This receptor is abundantly located throughout the body's organs, potentially resulting in shedding of the virus in feces. Despite viral transcripts being observed in feces days after symptoms have been clear, there have no reported cases of fecal-oral transmission.

Disease Manifestations

While SARS-CoV-2 infection has been noted at all ages, COVID-19 manifests largely in the elderly. Most infected people experience mild, flu-like symptoms.

For unknown reasons other individuals, especially older adults and people with certain comorbidities, develop acute respiratory distress syndrome (ARDS), the primary cause of death. Lung inflammation leads to domino effects across multiple organs that can lead to organ failure and eventually death.

Dysregulated Immune Response

A "cytokine storm," with very high levels of interleukin-6, precedes the development of ARDS. Most commonly seen in elderly patients, this storm occurs rapidly and unpredictably and can happen even in people who initially present with mild to moderate symptoms. The resulting immune pathology, instead of immune protection, has been linked to the rapid, overabundant recruitment, infiltration and activation of diverse innate immune cells within the lungs.

Several viral accessory genes have been implicated in this dysregulation of the immune response, especially the early innate immune sensing of the virus. Researchers are probing these genes to see if they represent therapeutic targets.

The "Goldilocks" Model of Immunity

Little is known about the correlates of immunity in SARS-CoV-2 infection. However, studies with other coronaviruses show that the immune response clearly demonstrates a "Goldilocks" model of immunity. While too small of an immune reaction can fail to protect the body from infection, a highly aggressive immune response can actually exacerbate disease through a process termed antibody-dependent enhancement.

Specifically, in the absence of antibodies, viruses can escape the innate immune response, infect their target, replicate, then disseminate. Conversely, with a too-large antibody response, multiple antibodies may bind the same virus particle, coating and protecting it, while they selectively deliver it to new target cells, thereby facilitating infection instead of preventing it.

In order to develop a vaccine that will be effective against such a highly infectious pathogen as SARS-CoV-2, there is an urgent need to define the precise correlates of immunity and the predictors of progression. Scientists will also need to find "the sweet spot"—the optimal balance of immunity, a response that is not too large and not too small.

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