Intranasal Inoculation of Cryptococcus neoformans in Mice Produces Nasal Infection with Rapid Brain Dissemination.

Carolina Coelho,Alexandre Alanio,Antonio Salas,Emma Camacho,Arturo Casadevall,Aaron P Mitchell

doi:10.1128/msphere.00483-19

Abstract

Cryptococcus neoformans is an important fungal pathogen, causing life-threatening pneumonia and meningoencephalitis. Brain dissemination of C. neoformans is thought to be a consequence of an active infection in the lung which then extravasates to other sites. Brain invasion results from dissemination via either transport by free yeast cells in the bloodstream or Trojan horse transport within mononuclear phagocytes. We assessed brain dissemination in three mouse models of infection: intravenous, intratracheal, and intranasal models. All three modes of infection resulted in dissemination of C. neoformans to the brain in less than 3 h. Further, C. neoformans was 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 of C. neoformans produces cryptococcal nasal infection. These findings imply that immunological studies using intranasal infection should assume that the initial sites of infection of infection are brain, lung, and upper respiratory tract, including the nasal airways.IMPORTANCECryptococcus neoformans causes an estimated 181, 000 deaths each year, mostly associated with untreated HIV/AIDS. C. neoformans has a ubiquitous worldwide distribution. Humans become infected from exposure to environmental sources, after which the fungus lays dormant within the human body. Upon AIDS-induced immunosuppression or therapy-induced immunosuppression (required for organ transplant recipients or those suffering from autoimmune disorders), cryptococcal disease reactivates and causes life-threatening meningitis and pneumonia. This study showed that upon contact with the host, C. neoformans can quickly (a few hours) reach the host brain and also colonizes the nose of infected animals. Therefore, this work paves the way to better knowledge of how C. neoformans travels through the host body. Understanding how C. neoformans infects, disseminates, and survives within the host is critically required so that we can prevent infections and the disease caused by this deadly fungus.

Highlights

Cryptococcus neoformans is an important fungal pathogen, causing lifethreatening pneumonia and meningoencephalitis
Intranasal infection has been accepted as a procedure for inducing pulmonary infection without much investigation as to what happens after nose deposition of an infective inoculum
We detected fungi in blood in two mice, we detected bacteria in blood in the same two mice. This suggests that the animals with C. neoformans in the blood had severe systemic infection that may have led to concomitant bacterial infection

Summary

Introduction

Cryptococcus neoformans is an important fungal pathogen, causing lifethreatening pneumonia and meningoencephalitis. In the 1950s, silent cryptococcal granulomas were reported in lungs, establishing a parallel to latent tuberculosis [4] In support of this notion, serological studies have established that adults have antibodies to C. neoformans [5] or delayed hypersensitivity skin reactions [6], consistent with asymptomatic infection. Researchers use a third route of infection, the intravenous (i.v.) route, since it allows rapid dissemination to the brain, presumably by bypassing the lung immune response [13, 14] Both the intranasal route [13] and the intravenous route (in outbred mice) have been shown to be a relevant model for comparisons to human infection [15,16,17]

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