About GSBS   |  FAQ  |  Job Opportunities  |  Search UMDNJ


Biochemistry and Molecular Biology Program
B.S. 2009, Montclair State University, Montclair, NJ

Thesis Advisor: Amariliz Rivera, Ph.D.
Assistant Professor
Department of Pediatrics

Tuesday, December 15, 2015
9:30 A.M., MSB C-600


Aspergillus fumigatus is a mold fungal pathogen and the most common cause
of invasive aspergillosis (IA), a serious infection that develops in patients with
compromised immune function. Although a variety of immune cells can help confer
protection against IA, the mechanisms that govern immune cell cooperation
culminating in the eradication of conidia and IA prevention are unclear. Among
innate cells, neutrophils have long been recognized as the sole essential
innate cells for defense against IA. In contrast, neutrophils are dispensable for
protection against Listeria monocytogenes or Toxoplasma gondii infection; in these
models CCR2+ inflammatory monocytes (CCR2+Mo) are instead essential innate cells
for protection. Given that neutrophils and CCR2+Mo are both recruited to the lung of
A.fumigatus infected mice, we set out to examine their relative contributions to
antifungal defense. We employed cell-specific ablation strategies to shown that in
addition to neutrophils, CCR2+Mo are essential, non-redundant, innate cells for the
prevention of IA. We find that upon A.fumigatus infection CCR2+Mo give rise to
monocyte-derived dendritic cells (MoDCs) and that the selective ablation of these
cells leads to uncontrolled fungal growth and mortality from IA. Our studies indicate
that CCR2+Mo and MoDCs are essential for: direct fungal spore eradication,
establishment of a protective inflammatory lung milieu, and the full activation of
neutrophil antifungal activities.
In order to determine how CCR2+Mo derived cells regulate neutrophil
antifungal effector functions, we performed an unbiased transcriptome analysis of
neutrophils that responded to a pulmonary A.fumigatus infection in the presence or
absence of CCR2+Mo and MoDC. Our analysis revealed that A.fumigatus infection
induces a strong type I and III IFN signature profile in antifungal neutrophils and that
removal of CCR2+Mo impairs this response. We confirmed these results through in
vivo studies, and determined that Type I and III IFN play non-redundant roles that are
necessary for host defense.
In order to determine if monocyte function is affected by the absence of
neutrophils just as neutrophils are affected by CCR2+Mo ablation, we selectively
depleted neutrophils in mice, which resulted in global transcriptional alterations of the
antifungal CCR2+Mo response, limited moDC differentiation, and diminished
conidiacidal activity. Impaired moDC antifungal activity in neutropenic mice was
accompanied by significant upregulation of carbonic anhydrase 4 (Car4) expression
in CCR2+Mo precursors. Pharmacological inhibition of Car4 with the FDA-approved
drug methazolamide (MZ) rescued the antifungal response of moDC and protected
neutropenic mice from invasive apergillosis. Thus, beyond their role as effectors,
antifungal neutrophils facilitate antifungal moDC functions by regulating Car4
Altogether, these data indicate that neutrophils and CCR2+Mo are
interdependent cells that cross-regulate each otherís antifungal effector functions. Our
studies provide novel mechanistic insight on how communication between these two
crucial innate cells orchestrates antifungal immunity in the lung.

Return to Dissertation list


Newark Campus - Piscataway Campus - Stratford Campus
About GSBS - FAQ - Job Opportunities - Search UMDNJ