Macrophages = lymphocyte frenemy?

Beginning in December 2019, a cluster of respiratory illness in Wuhan, China defined the onset of a worldwide pandemic involving a novel coronavirus, COVID-19 (COVID-19 is the name of the illness caused by this virus). Initial epidemiologic estimates from the WHO suggest that up to 20% of patients will develop severe disease and evidence of viral pneumonia; many of these patients will require ICU care and progress to develop acute respiratory distress syndrome (ARDS), shock and secondary organ failures, and super-infections. The virus that causes COVID-19, SARS-CoV-2, is thought to pass through the mucous membranes in the nose and throat and enter the lungs through the respiratory tract. As it migrates down the respiratory tract, the virus attacks organs that happen to express the natural protein receptor ACE2, which is found in the lungs, heart, kidneys, and intestines, and that normally exhibits a protective function. Once it infects and replicates within the cells of these organs, large numbers of viral particles are released, leading to cell death, a process known as “apoptosis”. To make matters worse, it is common to see patients, especially in aged and critically ill cases, who are hospitalized with COVID-19 to exhibit abnormally low levels of lymphocytes in their bloodstream. Lymphocytes are a critical subset of immune cells that help to fight infections. Without them, our bodies may no longer be able to resist the virus. The mechanism, a scientific word describing the specific details of a biologic response, remains unclear. As such, the authors conducted post-mortem autopsies on six COVID-19 patients and three healthy patients (who died from car crashes) to gain a better mechanistic understanding of lymphocyte depletion.

Imaging was used to detect ACE2 receptor expression in the spleens and lymph nodes of both COVID-19 patients and healthy controls, specifically on tissue-resident macrophages, which are a type of immune cell strategically positioned in the spleen and lymph nodes to intercept invading pathogens like viruses and bacteria. Simultaneously, the presence of SARS-CoV-2 was also detected in these tissue-resident macrophages, but not in lymphocytes. Evidence of both ACE2 receptor expression and SARS-CoV-2 presence suggest that virus-infected macrophages may play a central role in contributing to viral growth and spread. Gross pathological and histopathological observations of the spleens and lymph nodes for COVID-19 patients revealed severe tissue damage and, frequently, complete loss of germinal centers, areas where immune cells develop and reproduce. Closer examination confirms widespread lymphocyte apoptosis in these tissues compared to age-matched healthy controls. Finally, the authors looked at two potential mechanisms for the involvement of infected macrophages in triggering extensive lymphocyte apoptosis: (1) persistent activation of lymphocytes by presentation of the viral antigens, causing what is known as "activation-induced cell death (AICD)" through Fas-FasL interaction, and (2) secretion of pro-inflammatory cytokines that not only causes "cytokine storms" but can mediate lymphocyte apoptosis through IL-6 cytokine signaling. In support of the first potential mechanism, the expression of Fas was dramatically higher in virus-infected tissue compared to healthy controls. Similarly, IL-6 concentration was elevated in virus-infected splenic and lymph node tissues compared to healthy controls, which provides support for the second potential mechanism. Therefore, it is inferred that infected tissue-resident macrophages can trigger lymphocyte apoptosis by producing high-levels of IL-6 and enhancing Fas expression on its cell surface. In summary, the study reports that tissue-resident macrophages express ACE2 receptor and are susceptible to SARS-CoV-2 infection. These findings also point to a potential role that tissue-resident macrophages play in viral dissemination and immunopathology of the secondary lymphoid organs, and in the end, lymphocyte depletion.

There are still significant knowledge gaps in our understanding of disease development for COVID-19. In particular, the most severe cases of SARS-CoV-2 infection is characterized by "cytokine storms" in which high levels of pro-inflammatory immune cells and cytokines stimulate excessive inflammation, that then cause severe tissue damage. A better understanding of these pro-inflammatory immune cells and cytokines, including IL-6, as well as the deficient immune responses is still needed. In this study, the authors investigate the spleens and lymph nodes of COVID-19 patients and report severe damage, as well as identify the role of tissue-resident macrophages on hyperinflammation and lymphocytopenia. Given the role of IL-6 on disease progression, it will be important to investigate the effects that IL-6 inhibitors, like a medicine called tocilizumab, may have on splenic and lymph node function in COVID-19 patients. However, this study is not without limitations, and it should be noted that the study is limited by a small number of patients (6). 

See primary paper at https://www.medrxiv.org/content/10.1101/2020.03.27.20045427v1

By Vincent Chan