As one of the major targets of Covid-19, infection in the kidneys can led to significant complications associated with kidney disease, as well as kidney failure. Kidney damage can occur even in those that experience mild infection. The first installment of this two-part series identified a group of supportive cells within the kidneys, called podocytes, which are particularly vulnerable to infection and subsequent injury associated with SARS-CoV-2. To answer why stem cell-derived podocytes are so susceptible to infection, we must consider how the virus is able to bind and invade these host cells. Rather than ACE-2 receptors, Kalejaiye et al. found that binding to CD147 receptors on stem cell-derived kidney podocytes is the preferred mechanism through which SARS-CoV-2 infects these cells.

Here, we will continue discussing the significant findings from Kalejaiye et al., which may provide insight into how to protect not only the kidneys against infection but also other vulnerable cells and tissues throughout the body.

Early in the pandemic, angiotensin-converting enzyme 2, or ACE-2, was identified as a key binding site for SARS-CoV-2. Recent studies, however, have reported relatively low expression of ACE-2 receptors in the various tissues and organs that Covid-19 primarily infects, especially the lungs. Kalejaiye et al. were surprised to find that kidney podocytes express even lower levels of ACE-2 receptors. Compared to lung cells ACE-2 expression is 10 times lower in stem cell-derived kidney podocytes. These cells also expressed less of the TMPRSS2 enzyme, which normally works in tandem with ACE-2, than lung epithelial cells.

Given the low level of ACE-2 expression in many of these cells, CD147, also known as basigin or EMMPRIN, has been increasingly recognized as an alternative mechanism for viral infection. This transmembrane glycoprotein is a member of the immunoglobulin superfamily that promotes the recognition, binding, and adhesion of extracellular substances to the cell’s surface. CD147 receptors play a critical role in facilitating cell metabolism and communication, as well as regulating the responsiveness of lymphocytes. Studies indicate that these receptors are implicated in several infectious diseases, including Hepatitis B and C viruses and HIV.

Kalejaiye et al., therefore, speculated whether CD147 receptors may be the primary mechanism through which kidney podocytes are infected. They observed greater expression of these receptors in kidney podocytes, compared to both lung and colon cells. The degree of CD147 expression in kidney podocytes also correlated with the severity of infection, measured by how much viral content was detected in cells. Using antibodies to block these receptors reduced the rate of infection, suggesting that CD147 is a key receptor for SARS-CoV-2 binding and infection.

This does not mean that SARS-CoV-2 does not also act on ACE-2 receptors when infecting kidney podocytes. Blocking these ACE-2 receptors alone also reduced the severity of Covid-19 infection in these cells. Kalejaiye et al. in fact observed the lowest rates of infection when ACE-2, as well as CD147 receptors, were blocked. Therefore, it is likely that both ACE-2 and CD147 are involved in Covid-19 infection of kidney podocytes.

SARS-CoV-2 binding to ACE—2 and CD147 receptors may also be coregulated, in such a way that activity in one affects the expression of another. Kalejaiye et al. found that treating kidney podocytes with ACE-2 antibodies induced the downregulation of CD147, to a similar effect that CD147 antibodies decreased the expression of ACE-2 receptors. Nonetheless, blocking these receptors did not completely block infection, suggesting that more research is needed to identify other types of receptors that may facilitate SARS-CoV-2 binding and entry into the cell.

Understanding how the virus infects and enters cells can be a useful tool for identifying anti-viral targets for Covid-19. Although ACE-2 is widely recognized as a key receptor for SARS-CoV-2 binding, drugs that block these receptors may interfere with its various protective functions, including maintaining blood pressure and protecting against heart and kidney damage. Blocking CD147 proteins, on the other hand, may be able to reduce viral uptake, particularly in kidney podocytes, with relatively fewer side effects. However, we are just beginning to understand the complex role that CD147 plays in Covid-19. Future studies need to identify ways that drugs targeting both CD147 and ACE-2 can safely and effectively prevent SARS-CoV-2 infection.