Unlike SARS-CoV-1 and MERS-CoV,
infection with SARS-CoV-2, the viral pathogen responsible for
COVID-19, is often associated with
neurologic symptoms that range from mild to severe, yet increasing evidence argues the virus does not exhibit extensive neuroinvasive properties. We demonstrate SARS-CoV-2 can infect and replicate in human iPSC-derived neurons and that
infection shows limited
antiviral and inflammatory responses but increased activation of
EIF2 signaling following
infection as determined by
RNA sequencing. Intranasal
infection of
K18 human ACE2 transgenic mice (K18-hACE2) with SARS-CoV-2 resulted in lung pathology associated with viral replication and immune cell infiltration. In addition, ∼50% of infected mice exhibited
CNS infection characterized by wide-spread viral replication in neurons accompanied by increased expression of
chemokine (Cxcl9, Cxcl10, Ccl2, Ccl5 and Ccl19) and
cytokine (Ifn-λ and Tnf-α) transcripts associated with microgliosis and a neuroinflammatory response consisting primarily of monocytes/macrophages. Microglia depletion via administration of
colony-stimulating factor 1 receptor inhibitor,
PLX5622, in SARS-CoV-2 infected mice did not affect survival or viral replication but did result in dampened expression of proinflammatory
cytokine/
chemokine transcripts and a reduction in monocyte/macrophage infiltration. These results argue that microglia are dispensable in terms of controlling SARS-CoV-2 replication in in the K18-hACE2 model but do contribute to an inflammatory response through expression of pro-inflammatory genes. Collectively, these findings contribute to previous work demonstrating the ability of SARS-CoV-2 to infect neurons as well as emphasizing the potential use of the K18-hACE2 model to study immunological and neuropathological aspects related to SARS-CoV-2-induced neurologic disease. IMPORTANCE Understanding the immunological mechanisms contributing to both host defense and disease following
viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the role of microglia in aiding in host defense following experimental
infection of the central nervous system (CNS) of K18-hACE2 with SARS-CoV-2, the causative agent of
COVID-19.
Neurologic symptoms that range in severity are common in
COVID-19 patients and understanding immune responses that contribute to restricting neurologic disease can provide important insight into better understanding consequences associated with
SARS-CoV-2 infection of the CNS.