The normal host requires q • an intact cell-mediated immune system • a sufficient number of, and normally functioning, neutrophils to effect the normal response to the conidia we all continually encounter. The normal response is to clear conidia without establishment of an infectious nidus.
HOST DEFENSE vs. ASPERGILLUS 1. First line – pulmonary macrophages & monocyte-derived macs. a. Kill conidia, prevent germination by opsonin-independent nonoxidative method and oxidative method b. Depressed by glucocorticoids (not through T) c. CGD can do d. Not inc. by IFNg d. Not inc. by IFNg e. Conidia resist oxidative PMN also kill conidia by nonoxidative method (CGD PMN can). PMN also kill conidia by nonoxidative method (CGD PMN can). Lactoferrin seems important. In immunocompromised, PMN are critical at the time of challenge in the initial host response.
HOST DEFENSE vs. ASPERGILLUS 2. Second line – once germinated, PMN and monocytes kill hyphae a. Occurs even without opsonins b. Activation not needed, but could enhance c. Oxidative mechanism, defensins d. Depressed by corticoids (by dec. mobilization?); CSFs, IFNg reverse this effect on PMN, monos e. CGD PMN can’t f. Monocytes principally use H 2 O 2 , CGD results conflict g. T cells can damage hyphae, & potentiate PMN Serum is inhibitory at concs. >20% (Chiller et al.); controversial
N New player- Platelets l Pl t l t S Serotonin (5HT) is cidal to conidia & hyphae i (5HT) i id l idi & h h Platelets adhere to & spread over fungi. This Pl l dh & d f i Thi activates the platelets (markers) , & they degranulate This affects cell wall modeling, which damages the hyphae. h h h C. Lass-Florl C. Lass Florl
Additional points about host defenses and p Aspergillus Anti-defense by Aspergillus Anti defense by Aspergillus Conidia produce a catalase & an inhibitor of mac. oxidative burst & of i hibi f id i b f pro-inflammatory cytokine production H Hyphae produce proteases, phospholipases, h d t h h li gliotoxin (inhibits macs. & lyms.)
Innate mediators of host resistance: The Collectins The Collectins - Pattern recognition molecules Pattern recognition molec les These are collagenous carbohydrate-binding proteins Lung Surfactant Protein A (SP-A) and SP-D Mannose Binding Lectin-MBL
Aspergillosis and Collectins- SP-A, SP-D A ill i d C ll i SP A SP D Bind to mannose & maltose Aggregate conidia � � PMN oxidative burst Function by binding to cell or conidia receptor? KO- SP-D more important Rx purified human SP-D or rSP-D � � survival Steroid suppressed pul. murine model.
Aspergillus and collectins- MBL Aspergillus and collectins MBL • MBL binds to conidia, agglutinates them, inc. C4b deposition, i inc. PMN phagocytosis & oxidative burst, +/- inc. killing PMN h t i & id ti b t +/ i killi • MBL deficiency (mice) didn’t affect survival, but mice have 2 types & may’ve had enough of other types, & may ve had enough of other • Cortisone s ppressed p l aspergillosis Cortisone-suppressed pul. aspergillosis in BALB/c – Rx with rhMBL i.n. enhanced survival and reduced pulmonary fungal burden Treated mice showed ↑ TNF α , IL1 β & IFN γ ; ↓ IL10 γ ; – , β Suggests role for MBL in resistance and therapy Kaur, et al. 2007. Clin Exp Immunol. 148:382-89.
Systemic Aspergillosis in MBL KO Mice MBL KO and WT B6 mice Infected i.v. with A. fumigatus. MBL KO mice were LESS susceptible to systemic MBL KO mice were LESS susceptible to systemic infection! Further study needed to assess innate role of MBL in pulmonary disease Clemons, et al. ICAAC 2008
Collectins mannose binding lectin SP-A SP A SP-D pentraxin 3 may help phagocytes by acting as opsonins. Some also are directly cytotoxic cytotoxic. Production of chemokines may call on the appearance of other phagocytes at the local site. If, because of insufficiencies in phagocyte number or function a , p g y more durable response is needed, the innate immune system will become further engaged and initiate the engagement of the adaptive immune system immune system.
Triggering the innate immune system Conidia as they germinate expose β -glucan β -glucan triggers the innate immune system thru Dectin receptors, initiating an inflammatory response D ti t i iti ti i fl t H However, after conversion to hyphae, as hyphae mature ft i t h h h h t the exposure of β -glucan decreases
The fungus is recognized by Toll-like receptors (TLR). This encounter in dendritic cells (DC) appears to be critical for This encounter in dendritic cells (DC) appears to be critical for subsequent coordination of the immune system. If If conidia haven’t been contained by phagocytes, and some idi h ’t b t i d b h t d germinated into hyphae, the latter may subvert the development of the appropriate response.
The attachment of the fungal forms to different DC receptors -probably mannose receptors for conidia & CR3 for hyphae & CR3 for hyphae and the different methods of DC phagocytosis of the different fungal forms may lead to different DC signals and thus to different cytokine patterns thus to different cytokine patterns.
The DC take the internalized fungi to regional lymph nodes. The DCs mature express MHC II process antigen; which TLR path The DCs mature, express MHC II, process antigen; which TLR path triggered likely determines which co-stimulatory molecules are expressed, & thus whether Th1 or Th2 pathways ensue. The cytokines initially produced by the naïve phagocytes may also direct DC path. p
The adaptive immune system, largely represented by T cells, is engaged. p y , , g g g y p y T cells, in context of MHC, become activated, and proceed to elaborate either Th1 or Th2 dominant cytokines thus determining the adaptive either Th1- or Th2-dominant cytokines, thus determining the adaptive response. Regulatory T cells likely have an important role in inhibiting the development of allergy.
Patients responding to R ha e strong Th1 Patients responding to Rx have strong Th1 lymphoproliferative responses and high IFN γ /IL-10 ratios ratios. Passive transfer Passive transfer (animal expts.) of Th1 cells is protective. of Th1 cells is protective
The key cytokines associated with a successful y y response to Aspergillus infection are the proinflammatory and Th1 cytokines: p y y IFN γ IL-1 TNF α IL-6 IL-12 IL-18 GM-CSF Their production, rather than down-regulation of Th2 cytokines IL-4 & IL-10, appears to be even more important. p .
Mononuclear cells produce IFN γ , GM-CSF, TNF α & IL-2 in response to conidia. TNF & IL 2 i idi Studies suggest Th-1 stimulating antigens are in gg g g conidia, hyphal components favor Th2 path (for hyphal components favor Th2 path (for both human & murine cells).
Th2 In contrast, progressive invasive infection is associated with enhanced production of IL-4, associated with enhanced production of IL 4, IL-10, IgE, and depressed IFN γ
IL-17 -new story! Th17 cells now thought to be separate lineage of effector Th cells contributing to immune pathogenesis effector Th cells contributing to immune pathogenesis previously attributed to Th1 produce IL-17 promote neutrophil-mediated inflammation linked to resistance to several bacterial & parasitic infections also correlate with disease severity & immunopathology also correlate with disease severity & immunopathology L. Romani, Advances Against Aspergillosis 2008
Th17, not uncontrolled Th1, assoc. w. defective fungal clearance, failure to resolve inflammation, failure to i iti t initiate protective responses. t ti IL-17 & IL-23 inhibit PMN fungicidal activity & decrease inflammation even in presence of IFNg, decrease inflammation even in presence of IFNg suggesting Th17 prevails over Th1 Blocking IL-17 & IL-23 decreases PMN ingress, g g , prevents pathogenic inflammatory responses, ameliorates infection, restores protectiveTh1 antifungal resistance
One experimental way to study what genes are turned on in the immune response- example: turned on in the immune response example: Transcription Analysis of Murine Transcription Analysis of Murine Kidney and Brain in Response to Systemic Aspergillosis Juergen Loeffler 1 , Karl V. Clemons 3 , Michael Bonin 2 , g Sven Poths 2 , Hermann Einsele 1 , David A. Stevens 3 1 University of Wuerzburg, Medizinische Klinik II, Wuerzburg, Germany 2 University of Tuebingen Microarray Facility Tuebingen Germany 2 University of Tuebingen, Microarray Facility, Tuebingen, Germany 3 Santa Clara Valley Medical Center, San Jose, CA, USA
Aims of the study: • Perform genome-wide expression profiling for transcriptional host-response in p g p p kidney and brain of mice infected with A. fumigatus g •Compare gene expression profiles of uninfected and infected mice uninfected and infected mice • Compare expression profiles of infected mice to transcriptional response of human dendritic cells to A. fumigatus
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