SARS-CoV-2 could originate from unknown bats or intermediate hosts and cross the species barrier to humans. Virus-host interactions affect viral entry and replication. The virus genome encodes four essential structural proteins, the spike glycoprotein, the small envelope protein, the matrix proteins, and the nucleocapsid protein. The SARS-CoV-2 glycoprotein S binds to the host cell receptors of the enzyme, the conversion of angiotensin 2 (ACE2), which is a critical step for virus entry. It is expressed more in men than in women, probably by estradiol and testosterone that can influence ACE activity in different ways. In the viremia phase, it passes from the salivary glands and mucous membranes, especially the nasal and larynx, to the lungs and other organs with the same ACE2 receptors, such as the heart, liver, and even the central nervous system. It can reach the intestines, which can explain the symptoms and is detected in the stool from the beginning of the infection. Comorbidities such as immunodeficient status, old age, systemic arterial hypertension, diabetes mellitus or chronic lung diseases, obesity or smoking are key to viral pathogenesis. When the immune system is inefficient to effectively control the virus in the acute phase, it can evolve into a macrophage activation syndrome that results in the dreaded cytokine storm that puts the patient in a very critical condition. Understanding the pathophysiology of SARS-CoV-2 infection is the cornerstone to provide timely diagnosis and implement appropriate treatment for patients, limiting the spread of the virus and ultimately eliminating the presence of the virus in humanity.

KEYWORDS: SARS-CoV-2; Viral entry; Virus Genome; Nucleocapsid Protein; ACE2; Estradiol; Testosterone; Viremia; Macrophage Activation Syndrome; Host Microbial Interactions; Severe Acute Respiratory Syndrome.