Effect of CARD9 Deficiency on Neutrophil-Mediated Host Defense against Pulmonary Infection with Streptococcus pneumoniae

Abstract

Streptococcus pneumoniae is a major causative bacterium of community-acquired pneumonia. Dectin-2, one of the C-type lectin receptors (CLRs), was previously reported to play a pivotal role in host defense against pneumococcal infection through regulating phagocytosis by neutrophils while not being involved in neutrophil accumulation. In the present study, to elucidate the possible contribution of other CLRs to neutrophil accumulation, we examined the role of CARD9, a common adaptor molecule for signal transduction triggered by CLRs, in neutrophilic inflammatory response against pneumococcal infection. Wild-type (WT), CARD9 knockout (KO), and Dectin-2KO mice were infected intratracheally with pneumococcus, and the infected lungs were histopathologically analyzed to assess neutrophil accumulation at 24 h post-infection. Bronchoalveolar lavage fluids (BALFs) were collected at the same time point to count the neutrophils and assess the production of inflammatory cytokines and chemokines. Neutrophil accumulation was significantly decreased in CARD9KO mice, but not in Dectin-2KO mice. TNF-α, KC and MIP-2 production in BALFs were also attenuated in CARD9KO mice, but not in Dectin-2KO mice. Production of TNF-α and KC by alveolar macrophages stimulated with pneumococcal culture supernatants were significantly attenuated in CARD9KO mice, but not in Dectin-2KO mice, compared to each group's respective control mice. In addition, pneumococcus-infected CARD9KO mice showed larger bacterial burdens in the lungs than WT mice. These data indicate that CARD9 is required for neutrophil migration after pneumococcal infection as well as inflammatory cytokine and chemokine production by alveolar macrophages and suggest that a CLR distinct from Dectin-2 may be involved in this response.

CARD9 in host immunity to fungal, bacterial, viral, and parasitic infections: An update

“…Previous publications have revealed that Dectin-2 served as a critical regulator in host immunity against Streptococcus pneumoniae infection by affecting phagocytosis of neutrophils but excluding the recruitment of neutrophils (McGreal et al, 2006 ; Akahori et al, 2016 ). At present, Ishizuka et al ( 2020 ) found that CARD9 KO mice other than dectin-2 KO mice showed impaired neutrophil recruitment and decreased inflammatory cytokine and chemokine production compared to respective control mice. They indicated that CARD9-mediated signaling was indispensable in anti- pneumococcal immunity through modulating neutrophil function and cytokine production, in which both neutrophil phagocytosis and neutrophil accumulation required the participation of CARD9.…”

Deficiency of lung-specific claudin-18 leads to aggravated infection with Cryptococcus deneoformans through dysregulation of the microenvironment in lungs

“…Mice were sacrificed at various timepoints after infection. Bronchoalveolar lavage fluids (BALFs) were prepared as previously described 34 , 35 . After the BALFs were collected, lung homogenates were prepared as previously described 11 , 30 – 33 .…”

Role of CARD9 in Cell- and Organ-Specific Immune Responses in Various Infections

“…CARD9 is involved in immune signaling linked to bacterial infections through TLRs (TLR2 and TLR4) and NLRs (NOD1 and NOD2) [ 5 ]. Additionally, CLR signaling contributes to antibacterial immunity [ 52 , 53 , 54 ]. NODs collaborate with CARD9 to facilitate the recognition of bacterial peptidoglycan monosaccharide units known as muramyl dipeptide (MDP).…”

“…CARD9-deficient mice showed reduced specific-immune cell infiltration in the lungs compared to the wild type in response to pneumococcal infection; specifically, the number of neutrophils was significantly reduced compared to the wild type, but the number of macrophages was not altered [ 54 ]. This is because the cytokines and chemokines involved in neutrophil recruitment are reduced by CARD9 deficiency [ 54 ].…”