Therapeutic effects of recombinant forms of full-length and truncated human surfactant protein D in a murine model of invasive pulmonary aspergillosis.
Aspergillus fumigatus (Afu) is an opportunistic fungal pathogen that can cause fatal invasive pulmonary aspergillosis (IPA) in immunocompromised individuals. Previously, surfactant protein D (SP-D), a surfactant-associated innate immune molecule, has been shown to enhance phagocytosis and killing of Afu conidia by phagocytic cells in vitro. An intranasal treatment of SP-D significantly increased survival in a murine model of IPA. Here we have examined mechanisms via which recombinant forms of full-length (hSP-D) or truncated human SP-D (rhSP-D) offer protection in a murine model of IPA that were immunosuppressed with hydrocortisone and challenged intranasally with Afu conidia prior to the treatment. SP-D or rhSP-D treatment increased the survival rate to 70% and 80%, respectively (100% mortality on day 7 in IPA mice), with concomitant reduction in the growth of fungal hyphae in the lungs, and increased levels of TNF-alpha and IFN-gamma in the lung suspension supernatants, as compared to untreated IPA mice. The level of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the lung cell suspension was also raised considerably following treatment with SP-D or rhSP-D. Our results appear to reaffirm the notion that under immunocompromised conditions, human SP-D or its truncated form can offer therapeutic protection against fatal challenge with Afu conidia challenge. Taken together, the SP-D-mediated protective mechanisms include enhanced phagocytosis by recruited macrophages and neutrophils and fungistatic properties, suppression of the levels of pathogenic Th2 cytokines (IL-4 and IL-5), enhanced local production of protective Th1 cytokines, TNF-alpha and IFN-gamma, and that of protective C-C chemokine, MIP-1 alpha.
Singh
Mamta
M
Institute of Genomics and Integrative Biology, Council for Scientific and Industrial Research, Mall Road, Delhi 110007, India.
Madan
Taruna
T
Waters
Patrick
P
Sonar
Sanchaita
S
Singh
Shiv K
SK
Kamran
Mohammad F
MF
Bernal
Andrés López
AL
Sarma
P Usha
PU
Singh
Vijay K
VK
Crouch
Erika C
EC
Kishore
Uday
U
D000818:Animals; D001232:Aspergillus fumigatus; D054405:Chemokine CCL3 / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D037663:Pulmonary Surfactant-Associated Protein D / Q000235:genetics / Q000502:physiology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D037663:Pulmonary Surfactant-Associated Protein D; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma