Intranasal inoculation ofCryptococcus neoformansin mice produces nasal infection with rapid brain dissemination

Abstract

AbstractCryptococcus neoformansis an important fungal pathogen, causing life-threatening pneumonia and meningoencephalitis. Brain dissemination ofC. neoformansis thought to be a consequence of an active infection in the lung which then extravasates to other sites. Brain invasion results from dissemination via the bloodstream, either by free yeast cells in bloodstream or Trojan horse transport within mononuclear phagocytes. We assessed brain dissemination in three mouse models of infection: intravenous, intratracheal, and intranasal. All three modes of infection resulted in dissemination ofC. neoformansto the brain in under 3 hours. Further,C. neoformanswas detected in the entirety of the upper respiratory tract and the ear canals of mice. In recent years, intranasal infection has become a popular mechanism to induce pulmonary infection because it avoids surgery but our findings show that instillation ofC. neoformansproduces cryptococcal nasal infection. These findings imply that immunological studies using intranasal infection should assume the initial sites of infection of infection are brain, lung and upper respiratory tract, including the nasal airways.ImportanceCryptococcus neoformanscauses an estimated 181, 000 deaths each year, mostly associated with untreated HIV/AIDS.C. neoformanshas a ubiquitous worldwide distribution. Humans become infected from exposure to environmental sources and the fungus lays dormant within the human body. Upon immunosuppression, such as AIDS or therapy-induced as required by organ transplant recipients or autoimmune disease patients, cryptococcal disease reactivates and causes life-threatening meningitis and pneumonia. This study has detected that upon contact with the host,C. neoformanscan quickly (a few hours) reach the host brain and will also colonize the nose of infected animals. Therefore, this work paves the way to better knowledge of howC. neoformanstravels through the host body. Understanding howC. neoformansinfects, disseminates and survives within the host is critically required so that we can prevent infections and the disease caused by this deadly fungus.