TY - JOUR
T1 - Aspergillus fumigatus preexposure worsens pathology and improves control of Mycobacterium abscessus pulmonary infection in mice
AU - Monin, Leticia
AU - Mehta, Shail
AU - Elsegeiny, Waleed
AU - Gopal, Radha
AU - McAleer, Jeremy P.
AU - Oury, Tim D.
AU - Kolls, Jay
AU - Khader, Shabaana A.
N1 - Funding Information:
This work was supported by funds from Washington University in St. Louis to S. A. Khader, a CF Foundation Pilot Grant to S. A. Khader and J. Kolls (Research and Development Program from the CF Foundation CFF/FRIZZE15R0), NIH grant HL105427 to S. A. Khader, funds from Children’s Hospital of Pittsburgh and a Research Advisory Committee Grant from Children’s Hospital of Pittsburgh to L. Monin, and an NIH T32 HL007317 pulmonary training grant to S. Mehta.
Publisher Copyright:
© 2018 American Society for Microbiology.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Mutations in this chloride channel lead to mucus accumulation, subsequent recurrent pulmonary infections, and inflammation, which, in turn, cause chronic lung disease and respiratory failure. Recently, rates of nontuberculous mycobacterial (NTM) infections in CF patients have been increasing. Of particular relevance is infection with Mycobacterium abscessus, which causes a serious, life-threatening disease and constitutes one of the most antibiotic-resistant NTM species. Interestingly, an increased prevalence of NTM infections is associated with worsening lung function in CF patients who are also coinfected with Aspergillus fumigatus. We established a new mouse model to investigate the relationship between A. fumigatus and M. abscessus pulmonary infections. In this model, animals exposed to A. fumigatus and coinfected with M. abscessus exhibited increased lung inflammation and decreased mycobacterial burden compared with those of mice infected with M. abscessus alone. This increased control of M. abscessus infection in coinfected mice was mucus independent but dependent on both transcription factors T-box 21 (Tbx21) and retinoic acid receptor (RAR)- related orphan receptor gamma t (RORγ-t), master regulators of type 1 and type 17 immune responses, respectively. These results implicate a role for both type 1 and type 17 responses in M. abscessus control in A. fumigatus-coinfected lungs. Our results demonstrate that A. fumigatus, an organism found commonly in CF patients with NTM infection, can worsen pulmonary inflammation and impact M. abscessus control in a mouse model.
AB - Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Mutations in this chloride channel lead to mucus accumulation, subsequent recurrent pulmonary infections, and inflammation, which, in turn, cause chronic lung disease and respiratory failure. Recently, rates of nontuberculous mycobacterial (NTM) infections in CF patients have been increasing. Of particular relevance is infection with Mycobacterium abscessus, which causes a serious, life-threatening disease and constitutes one of the most antibiotic-resistant NTM species. Interestingly, an increased prevalence of NTM infections is associated with worsening lung function in CF patients who are also coinfected with Aspergillus fumigatus. We established a new mouse model to investigate the relationship between A. fumigatus and M. abscessus pulmonary infections. In this model, animals exposed to A. fumigatus and coinfected with M. abscessus exhibited increased lung inflammation and decreased mycobacterial burden compared with those of mice infected with M. abscessus alone. This increased control of M. abscessus infection in coinfected mice was mucus independent but dependent on both transcription factors T-box 21 (Tbx21) and retinoic acid receptor (RAR)- related orphan receptor gamma t (RORγ-t), master regulators of type 1 and type 17 immune responses, respectively. These results implicate a role for both type 1 and type 17 responses in M. abscessus control in A. fumigatus-coinfected lungs. Our results demonstrate that A. fumigatus, an organism found commonly in CF patients with NTM infection, can worsen pulmonary inflammation and impact M. abscessus control in a mouse model.
KW - Aspergillus
KW - Cystic fibrosis
KW - Cytokines
KW - Nontuberculous mycobacterium
KW - Pulmonary immunity
UR - http://www.scopus.com/inward/record.url?scp=85042303000&partnerID=8YFLogxK
U2 - 10.1128/IAI.00859-17
DO - 10.1128/IAI.00859-17
M3 - Article
C2 - 29263106
AN - SCOPUS:85042303000
VL - 86
JO - Infection and Immunity
JF - Infection and Immunity
SN - 0019-9567
IS - 3
M1 - e00859-17
ER -