Genetic Variation in <i>SP-A2</i> Leads to Differential Binding to <i>Mycoplasma pneumoniae</i> Membranes and Regulation of Host Responses

Ledford, Julie G.; Voelker, Dennis R.; Addison, Kenneth J.; Wang, Ying; Nikam, Vinayak; Degan, Simone; Kandasamy, Pitachaimani; Tanyaratsrisakul, Sasipa; Fischer, Bernard M.; Kraft, Monica; Hollingsworth, John W.

doi:10.4049/jimmunol.1500104

Cited by 19 publications

(31 citation statements)

References 42 publications

(48 reference statements)

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“…Because some lipopeptides, including FSL‐1 and Pam3CSK4, have shown to induce NETs release via TLR2 (Marcos et al, ), the receptor might participate in the induction of NETs release by M. pneumoniae . In contrast, early studies have shown that M. pneumoniae induces inflammatory responses independently of TLR2 (Chmura et al, ; Shimizu et al, ; Ledford et al, ), suggesting that receptors other than TLR2 may also take a part in the NETs release from neutrophils upon M. pneumoniae infection.…”

Section: Discussionmentioning

confidence: 91%

Mpn491, a secreted nuclease ofMycoplasma pneumoniae, plays a critical role in evading killing by neutrophil extracellular traps

Yamamoto

Kida

Sakamoto

et al. 2016

Cellular Microbiology

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Neutrophils play an important role in antimicrobial defense as the first line of innate immune system. Recently, the release of neutrophil extracellular traps (NETs) has been identified as a killing mechanism of neutrophils against invading microbes. Mycoplasma pneumoniae, a causative agent of respiratory infection, has been shown to be resistant to in vitro killing by neutrophils, suggesting that the bacterium might circumvent bactericidal activity of NETs. In this study, we investigated whether M. pneumoniae possesses resistance mechanisms against the NETs-mediated killing of neutrophils and found that the bacterium degrades the NETs induced upon M. pneumoniae infection. The NETs-degrading ability of M. pneumoniae required the production of a secreted nuclease, Mpn491, capable of using Mg as a cofactor for its hydrolytic activity. Moreover, the inactivation of the nuclease resulted in increased susceptibility of M. pneumoniae to the NETs-mediated killing of neutrophils. The results suggest that M. pneumoniae employs Mpn491 as a means for evading the killing mechanism of neutrophils.

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Section: Discussionmentioning

confidence: 91%

Mpn491, a secreted nuclease ofMycoplasma pneumoniae, plays a critical role in evading killing by neutrophil extracellular traps

Yamamoto

Kida

Sakamoto

et al. 2016

Cellular Microbiology

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“…According to a recent study, phosphorylation of EGFR was increased in the lungs by mycoplasma membrane fraction stimulation in SP-A knock-out mice (36). These results suggested that SP-A down-regulates EGFR activity in vivo.…”

Section: Sp-a Down-regulates Egf Signalingmentioning

confidence: 90%

Surfactant protein A down-regulates epidermal growth factor receptor by mechanisms different from those of surfactant protein D

Hasegawa¹,

Takahashi²,

Ariki³

et al. 2017

Journal of Biological Chemistry

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We recently reported that the lectin surfactant protein D (SP-D) suppresses epidermal growth factor receptor (EGFR) signaling by interfering with ligand binding to EGFR through an interaction between the carbohydrate-recognition domain (CRD) of SP-D and -glycans of EGFR. Here, we report that surfactant protein A (SP-A) also suppresses EGF signaling in A549 human lung adenocarcinoma cells and in CHOK1 cells stably expressing human EGFR and that SP-A inhibits the proliferation and motility of the A549 cells. Results withI-EGF indicated that SP-A interferes with EGF binding to EGFR, and a ligand blot analysis suggested that SP-A binds EGFR in A549 cells. We also found that SP-A directly binds the recombinant extracellular domain of EGFR (soluble EGFR or sEGFR), and this binding, unlike that of SP-D, was not blocked by EDTA, excess mannose, or peptide:-glycosidase F treatment. We prepared a collagenase-resistant fragment (CRF) of SP-A, consisting of CRD plus the neck domain of SP-A, and observed that CRF directly binds sEGFR but does not suppress EGF-induced phosphorylation of EGFR in or proliferation of A549 cells. These results indicated that SP-A binds EGFR and down-regulates EGF signaling by inhibiting ligand binding to EGFR as well as SP-D. However, unlike for SP-D, SP-A lectin activity and EGFR -glycans were not involved in the interaction between SP-A and EGFR. Furthermore, our results suggested that oligomerization of SP-A is necessary to suppress the effects of SP-A on EGF signaling.

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“…We used a total of 10 C57BL/6 mice, 5 SP‐A (−/−) knockouts and 5 humanized transgenic (hTG) SP‐A2 knockins (+/−) . The animals were euthanized by CO 2 asphyxiation and whole nasal meatuses were harvested and snap frozen with liquid nitrogen followed by Bessman tissue pulverization.…”

Section: Methodsmentioning

confidence: 99%

Novel role of surfactant protein A in bacterial sinusitis

Noutsios

Willis

Ledford

et al. 2017

Int Forum Allergy Rhinol

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Background Chronic rhinosinusitis (CRS) is a common inflammatory disorder of the upper airway characterized by chronic inflammation and significant sinonasal remodeling. CRS has two major subgroups based on whether polyps are present or absent. In some cases, it is characterized by colonization with opportunistic pathogens such as Pseudomonas aeruginosa (PA), Staphylococcus aureus and other bacteria. The innate immune system of the sinonasal epithelium is the first line of defense against inhaled pathogens. Surfactant protein A (SP-A) is a member of the collectin family secreted by the airway epithelia that plays a critical role in airway innate immunity, as it can aggregate bacteria. We hypothesized that SP-A plays a role in bacterial CRS. Methods Air-liquid-interface (ALI) cultures of nasal epithelial cells were derived from human ex vivo healthy and CRS sinus tissues (n=26) and challenged with PA. SP-A levels were measured with Western Blot and qRT-PCR in ALI and sinus tissues. Results We determined that SP-A i) mRNA and protein levels are significantly increased in CRS tissues compared to healthy sinuses; ii) although primary expressed in the lung, it is also synthesized and expressed in sinonasal epithelia; ii) is expressed in the sinuses of an SP-A humanized transgenic mouse but not in SP-A knock-out mouse; iv) mRNA levels are upregulated significantly during PA challenge, but protein levels are downregulated 4h post challenge and upregulated at 12h. Conclusions Our data suggest that SP-A is expressed in the sinuses and it plays a role in the sinus innate immune responses during bacterial infections.

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Genetic Variation in SP-A2 Leads to Differential Binding to Mycoplasma pneumoniae Membranes and Regulation of Host Responses

Cited by 19 publications

References 42 publications

Mpn491, a secreted nuclease ofMycoplasma pneumoniae, plays a critical role in evading killing by neutrophil extracellular traps

Mpn491, a secreted nuclease ofMycoplasma pneumoniae, plays a critical role in evading killing by neutrophil extracellular traps

Surfactant protein A down-regulates epidermal growth factor receptor by mechanisms different from those of surfactant protein D

Novel role of surfactant protein A in bacterial sinusitis

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