**Abstract**

Coronavirus disease 2019 (COVID-19) and its etiological agent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have caused considerable illness and death worldwide. The innate immune system seems to play a principal in the disease, as a hallmark of severe COVID-19 is excessive inflammation. Monocytes and macrophages are important innate immune cells that become pro-inflammatory and promote adaptive immune responses during viral infection. In this chapter we present evidence linking these cells to severity of COVID-19. Namely, monocytes and macrophages infiltrate the infected tissue during the early stages of infection and show pro-inflammatory responses that appear to be linked to those predicting tissue pathology during disease. Additionally, studies in isolated cells demonstrate that monocytes and macrophages respond by producing pro-inflammatory cytokines when directly stimulated by SARS-CoV-2. While most anti-inflammatory pharmaceutical treatments for COVID-19 have focused on systemic infiltration, some of the most promising have known or suspected effects on monocyte and macrophage inflammatory responses. Therefore, targeting these cells to treat severe COVID-19 is a promising strategy for this important disease.

**Keywords:** COVID-19, SARS-CoV-2, monocytes, macrophages, innate immunity

### **1. Introduction**

A novel highly pathogenic coronavirus emerged in Hubei Province, China in the latter months of 2019. The government of the People's Republic of China informed the World Health Organization of the outbreak of the virus, which was preliminarily named novel coronavirus 2019 (2019-nCov), on 31 December 2019. Early observational studies found high incidences of fever, cough, and fatigue in hospitalized patients with diagnosed infection, and pneumonia, acute respiratory distress syndrome, and higher plasma pro-inflammatory cytokine levels were also common in those admitted to the Intensive Care Unit [1]. Comorbidities including older age and diabetes were found to be associated with worse outcomes [2].

Patient samples were utilized to isolate a betacoronavirus which was distinct from previous highly pathogenic coronaviruses such as Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), which caused epidemic outbreaks in 2002–2003 [3] and 2012 [4] respectively. Molecular epidemiology studies on 2019-nCov found that the new virus shared approximately 80% sequence identity to SARS-CoV, and further that it shared ~96% sequence identity to the known bat coronavirus RaTG13 [5], suggesting a potential bat origin. Later papers have suggested transmission to

humans through an intermediate host, with leading candidates including Malayan pangolins and minks [6], but to date no natural viral reservoir or intermediate host has been found despite extensive surveys. Although there has been some speculation as to a laboratory origin of 2019-nCov, this is generally rejected by most in the scientific community [7–10], and to date there is no compelling evidence of a human origin for the virus.

In March 2020, the World Health Organization declared a worldwide pandemic of Coronavirus Disease-2019 (COVID-19), the disease of which 2019-nCov is the etiological agent. Likewise in that month, the International Committee on Taxonomy of Viruses (ICTV) officially named the new virus the Severe Acute Respiratory Coronavirus-2 (SARS-CoV-2) [11], and this nomenclature will be utilized throughout the rest of the chapter. To date, SARS-CoV-2 and COVID-19 have caused tremendous morbidity and mortality worldwide, with deaths from COVID-19 numbering more than 3 million as of mid-April 2021 [12].

## **1.1 Clinical indicators of COVID-19**

COVID-19 generally presents with some combination of cough, fever, and/or dyspnea, with less prevalent symptoms including diarrhea, myalgia, and nausea/ vomiting [13]. Clinical immunology indicators of severe COVID-19 also include lymphopenia and thrombocytopenia [13] as well as significant elevations of circulating pro-inflammatory cytokines and other inflammation markers such as C-reactive protein [14]. Chest CT scans detect ground glass opacities and pneumonia in a substantial fraction of COVID-19 patients with severe disease [13, 15]. Severe COVID-19 can progress to acute respiratory distress syndrome [16] and can lead to death.

Multiple co-morbidities are associated with severity of COVID-19. Among these, advanced age is the strongest predictor of morbidity and mortality [17], and increased disease severity is also linked with pre-existing diabetes [18] and severe asthma [17]. In addition to the pulmonary system, SARS-CoV-2 has been found to infect other organ systems including the cardiovascular, central nervous, and gastrointestinal tract systems [19], therefore a variety of other symptoms can occur during COVID-19. A subset of COVID-19 patients develop persistent symptoms which last for weeks or months, which has been described as post-acute COVID-19 syndrome or colloquially as "long COVID" [20]. The etiology of long COVID is unknown, but does not appear to be associated with persistence of replicationcompetent SARS-CoV-2 [21].
