Cellular Immune Responses to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection in Senescent BALB/c Mice: CD4⁺T Cells Are Important in Control of SARS-CoV Infection

Abstract

The global outbreak of severe acute respiratory syndrome (SARS) in 2003 that infected more than 8,000 people in 29 countries across five continents, with 774 deaths reported by the World Health Organization (54), was caused by a highly contagious coronavirus designated SARS-CoV (33). The elderly were more likely to die from SARS-CoV infection than younger people (7), with a case-fatality rate of 50% in people older than 65 years (14, 53). Disease pathogenesis in SARS is complex, with multiple factors leading to severe pulmonary injury and dissemination of the virus to other organs. High viral load; systemic infection; a cytokine storm with high levels of CXCL10/IP-10, CCL3/MIP-1␣, and CCL2/MCP-1; massive lung infiltration by monocytes and macrophages; and rapid depletion of T cells are hallmarks of SARS (5,13,15,21,28,35). The role of neutralizing antibodies (Abs) in protection from SARS-CoV infection has been well documented. Virusspecific neutralizing Abs reduce viral load, protect against weight loss, and reduce histopathology in animal models (42,47,48). Although the role of type I interferons (IFNs) in the natural history of SARS is controversial (5, 9, 59), the innate defense system appears to be critical for controlling SARSCoV replication in mice (23, 41). Mice lacking normal innate signaling due to STAT1 or MyD88 deficiency are highly susceptible to SARS-CoV infection. Virus-specific T-cell responses are present in convalescent patients with SARS (27, 55). However, little is known about the role of T cells in the acute phase of SARS.Several mouse models have been developed for the in vivo study of SARS pathogenesis. However, no single model accurately reproduces all aspects of the human disease. SARS-CoV replicates in the upper and lower respiratory tracts of 4-to 8-week-old mice and is cleared rapidly; infection is associated with transient mild pneumonitis, and cytokines are not detectable in the lungs (20,42,49). A SARS-CoV isolate that was adapted by serial passage in mice (MA-15) replicates to a higher titer and for a longer duration in the lungs than the unadapted (Urbani) virus and is associated with viremia and mortality in young mice (36), but the histologic changes in the lungs are caused by high titers of virus and cell death without significant infiltrates of inflammatory cells. The heightened susceptibility of elderly patients to SARS led us to develop a pneumonia model in 12-to 14-month-old (mo) BALB/c mice using the Urbani virus. In this model, pulmonary replication of virus was associated with signs of clinical illness and histopathological evidence of disease characterized by bronchiolitis, interstitial pneumonitis, diffuse alveolar damage, and fibrotic scarring (3), thus resembling SARS in the elderly. We evaluated the host response to SARS-CoV infection by examining the gene expression profile in the senescent mouse model and found a robust response to virus infection, with an increased expression of several immune response and cell-to-cell

A Live Attenuated H7N7 Candidate Vaccine Virus Induces Neutralizing Antibody That Confers Protection from Challenge in Mice, Ferrets, and Monkeys

“…injection of anti-CD8 ϩ and/or CD4 ϩ Abs 3 days before and after lethal challenge with H7 wt viruses. We used a protocol for T-cell depletion that was previously shown to deplete these T-cell subsets (12,15). Despite the depletion of CD8 ϩ and/or CD4 ϩ T cells, all of the mice immunized with a single dose of the H7N7 NL/03 ca virus survived challenge with all three viruses, including the homologous NL/03 (H7N7) virus and the heterologous ck/BC/04 (H7N3) and tk/EG/63 (H7N3) wt viruses (data not shown).…”

“…Following 1 or 2 doses of the H7N7 NL/03 ca vaccine, CD4 ϩ and/or CD8 ϩ T cells were depleted in mice as described previously (12,15) by the intraperitoneal (i.p.) injection of 1 mg/ml of anti-CD4 Ab (clone GK 1.5) and/or 1 mg/ml of anti-CD8 Ab (clone 2.43) 3 days before and after lethal challenge with H7 wt viruses.…”

Aluminium hydroxide potentiates a protective Th1 biased immune response against polio virus that allows for dose sparing in mice and rats

“…Cellular immunity towards polio virus has received less attention due to compelling evidence that humoral immunity is the most important effector mechanism against polio. However, there are numerous examples showing that cellular immunity, besides being an effector mechanism in itself, can be important for humoral immunity [19][20][21][22][23][24][25], even humoral immunity against polio virus [26,27]. PBMCs were obtained from mice vaccinated with 2 DU IPV alone or IPV 2 DU + aluminium hydroxide two and five weeks following the booster vaccination.…”

Modulation of Immune System by Kaposi’s Sarcoma-Associated Herpesvirus: Lessons from Viral Evasion Strategies

“…LANA physically interacts with p53 to repress its transcriptional and translational activity (Friborg et al, 1999; Si and Robertson, 2006; Chen et al, 2010). Ultimately, LANA inhibits the ability of p53 to induce cell death, thereby, promoting chromosomal instability (Friborg et al, 1999; Si and Robertson, 2006).…”