Heme Oxygenase-1 Deficiency Diminishes Methicillin-Resistant Staphylococcus aureus Clearance Due to Reduced TLR9 Expression in Pleural Mesothelial Cells

作者：Gahlot Satindra; Nasreen Najmunnisa; Johnson Judith A; Sahn Steven A; Mohammed Kamal A^*

来源：PLos One, 2017, 12(1): e0169245.

DOI：10.1371/journal.pone.0169245

Methicillin Resistant Staphylococcus aureus (MRSA) cause pneumonia and empyema thoraces. TLR9 activation provides protection against bacterial infections and Heme oxygenase-1 (HO-1) is known to enhance host innate immunity against bacterial infections. However, it is still unclear whether HO-1 regulates TLR-9 expression in the pleura and modulates the host innate defenses during MRSA empyema. In order to determine if HO-1 regulates host innate immune functions via modulating TLR expression, in MRSA empyema, HO-1(+/+) and HO-1(-/-) mouse pleural mesothelial cells (PMCs) were infected with MRSA (1:10, MOI) in the presence or absence of Cobalt Protoporphyrin (CoPP) and Zinc Protoporphyrin (ZnPP) or CORM-2 (a Carbon monoxide donor) and the expression of mTLR9 and mBD14 was assessed by RT-PCR. In vivo, HO-1(+/+) and HO-1(-/-) mice were inoculated with MRSA (5x10(6) CFU) intra-pleurally and host bacterial load was measured by CFU, and TLR9 expression in the pleura was determined by histochemical-immunostaining. We noticed MRSA inducing differential expression of TLR9 in HO-1(+/+) and HO-1(-/-) PMCs. In MRSA infected HO-1(+/+) PMCs, TLR1, TLR4, and TLR9 expression was several fold higher than MRSA infected HO-1(-/-) PMCs. Particularly TLR9 expression was very low in MRSA infected HO-1(-/-) PMCs both in vivo and in vitro. Bacterial clearance was significantly higher in HO-1(+/+) PMCs than compared to HO-1(-/-) PMCs in vitro, and blocking TLR9 activation diminished MRSA clearance significantly. In addition, HO-1(-/-) mice were unable to clear the MRSA bacterial load in vivo. MRSA induced TLR9 and mBD14 expression was significantly high in HO-1(+/+) PMCs and it was dependent on HO-1 activity. Our findings suggest that HO-1 by modulating TLR9 expression in PMCs promotes pleural innate immunity in MRSA empyema.

• 出版日期2017-1-4