Smallpox caused by variola virus is acquired by respiratory route through inhalation of nasal, oral, or pharyngeal drop-lets. The infection can also be acquired by direct contact with infected skin or fomites. The virus enters the human host though the mucous membranes of the upper respiratory tract. The poxviruses encode many proteins, which initially stimu-late host cell growth and then lead to cell lysis and viral spread, thereby facilitating their replication in the cells, lysis of infected cells, and viral spread.
The virus replicates at the site of inoculation and spreads to lymph nodes draining the site of mucosal entry. The virus replicates in the lymphoid tissues, causes transient viremia, and infection of the reticuloendothelial cells. This is followed by a secondary phase of multiplication in these cells, lead-ing to a secondary viremia. This results in clinical manifesta-tions of the disease, which manifests as fever and other toxic manifestations. The viruses then enter the skin, localize in the blood vessels of the skin, and produce characteristic rash of the smallpox. The rash is due to the replication of virus in the skin followed by the damage caused by cytotoxic T cells, damaging the virus-infected cells.
Variola infection is characterized by development of both humoral and cellular immunities. Humoral immune response includes the appearance of hemagglutination inhibition (HI), complement fixing (CF), and neutralizing (NT) antibodies within first to third week of infection. The HI and CF antibody levels usually decrease within a year, whereas NT antibod-ies persist longer, for many years and decades after infection. Humoral antibodies are not protective. Cell-mediated immu-nity plays an important role in controlling and resolving the disease. Virus-specific T cells control the spread of viruses by causing lysis of infected cells in the reticuloendothelial cells in the skin. An attack of smallpox gives complete protection against reinfection. Vaccination confers immunity, which lasts about 10 years.