Impact of Candida auris infection in a neutropenic murine model

Abstract

Candida auris has become a global public health threat due to its multidrug resistance and persistence in hospital and nursing home settings. Although a skin colonizer, C. auris can cause fatal bloodstream infections and most patients succumb to multi-organ failure. Currently, there are limited animal models to study the progression of C. auris infection. Here we compare two murine models of neutrophil depletion using monoclonal antibodies 1A8, anti-Ly6G+ and RB6-8C5 anti-Ly6G+-Ly6C+. We also compare inoculums of 107 and 108 as well as the intravenous and gavage routes of infection. The results reveal that neutrophil depletion in BALB/c mice is sustained long-term with the 1A8 antibody and short-term with RB6-8C5. Target organs were kidney, heart and brain as these had the highest organ fungal burden in neutrophil depleted and to some extent in infected control mice. We found that C. auris is shed in urine and feces for neutrophil depleted mice. The gavage model is not an ideal route as dissemination was not detected. Eight days post C. auris infection all surviving mice display a unique behavioral phenotype characterized by torticollis and tail spin that progresses to head bobbing and body curling like phenotype by day 22, that continues to persist even 104 days post infection. Lastly, we found C. auris remains in tissues of infected control mice, 34 plus days post infection suggesting that C. auris stays present in the host without causing disease but becomes opportunistic upon a change in the hosts immune status such as neutrophil depletion.

Candida Cell-Surface-Specific Monoclonal Antibodies Protect Mice against Candida auris Invasive Infection

“…Within each clade, isolates may have differences in morphology, levels of virulence, growth rates, and antifungal-resistance profiles [ 4 , 32 ]. Being so, in preparation for our animal studies, we first investigated the antifungal susceptibility of two clinical isolates of C. auris belonging to distinct clades: AR-0386 (CAU-06) of Clade IV and AR-0389 (CAU-09) of Clade I. AR-0386 is a highly aggregative South American isolate that has been shown to be less virulent than C. albicans in mouse models [ 33 ], while AR-0389 is a nonaggregative South Asian isolate that is highly virulent in mouse models [ 31 , 34 ]. It has been reported that nonaggregating C. auris isolates such as AR-0389 are among the most virulent clinical isolates, with virulence comparable to that of C. albicans in the invertebrate Galleria mellonella model [ 35 ].…”

“…A/J mice are deficient in complement protein C5 and its cleaved product C5a, a pro-inflammatory chemoattractant important for anti- Candida protection [ 28 , 29 , 30 ]. This renders A/J mice highly susceptible to C. auris disseminated infection without the need for immunosuppressive drugs [ 31 ]. Using this model, we identified three mAbs that provided significant protection, as evidenced by extended survival and lower fungal burdens in the kidney, brain, and heart, compared to control mice.…”