The Paradoxical Effects of Serum Amyloid-P Component on Disseminated Candidiasis
Open accessAbstract
Serum amyloid P component (SAP) may play an important role in human fungal diseases. SAP binds to functional amyloid on the fungal surface and masks fungi from host immune processes, skewing the macrophage population from the pro-inflammatory M1 to the quiescent M2 type. We assessed the role of SAP in a murine model of disseminated candidiasis. Mice were injected with human SAP subcutaneously (SQ) followed by intravenous injection of Candida albicans. Male, BALBcJ mice were administered 2 mg human SAP or the homologous human pro-inflammatory pentraxin CRP, SQ on day −1 followed by 1 mg on days 0 thru 4; yeast cells were administered intravenously on day 0. Mice not receiving a pentraxin were morbid on day 1, surviving 4–7 days. Mice administered SAP survived longer than mice receiving yeast cells alone (p < 0.022), although all mice died. Mice given CRP died faster than mice receiving yeast cells alone (p < 0.017). Miridesap is a molecule that avidly binds SAP, following which the complex is broken down by the liver. Miridesap administered in the drinking water removed SAP from the serum and yeast cells and significantly prolonged the life of mice (p < 0.020). Some were “cured” of candidiasis. SAP administered early in the septic process provided short-lived benefit to mice, probably by blunting cytokine secretion associated with disseminated candidiasis. The most important finding was that removal of SAP with miridesap led to prolonged survival by removing SAP and preventing its dampening effects on the host immune response.
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CPHPC efficiently binds to SAP, leading to the dissociation of SAP from bound amyloids and subsequent depletion of SAP levels in the body.
“This compound efficiently binds to SAP, leading to the dissociation of SAP from bound amyloids and subsequent depletion of SAP levels in the body24,62–68.”
From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [62]
CPHPC (miridesap) at a concentration of 5 mg ml−1 in drinking water is an established dose for SAP depletion from the body.
“To examine the effects of CPHPC on age-associated bone changes, male and female mice aged 18 months were treated with CPHPC (miridesap) at a concentration of 5 mg ml−1 in drinking water, which is an established dose for SAP depletion from the body62–65,67,68,84.”
From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [62]
Several recent studies have reported that CPHPC is also effective in depleting SAP in mice in different disease models.
“However, consistent with our results in mice, several recent studies have reported that this drug is also effective in depleting SAP in mice in different disease models62,64.”
From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [62]
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Cites
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“Human SAP (2 mg) was administered SQ 18 h before the injection of fungi thus providing serum levels of SAP approximating the human serum concentration of SAP [22].”
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“SAP-dependent amelioration of disease following the inhalation of Aspergillus conidia had been shown to involve a dampening of the host response [19].”
BackgroundInfluentialImmunity to Invasive Fungal Diseases
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“Figure 2 shows representative images of the evolution of the infection in the kidney, a targeted organ in mice and humans following fungal access to the vasculature [24].”
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“more balanced response including moderate pro- and anti-inflammatory cytokine secretion [16,34].”
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“idiopathic pulmonary fibrosis, long-term intravenous treatment with pharmacologic doses of recombinant human SAP stabilizes pulmonary function in patients [7].”
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“The SAP concentration can rise significantly following infection or inflammation and mice strains with lower basal concentrations of SAP undergo an increase in SAP to equal the concentrations of those strains with higher basal concentrations following an acute phase response [31].”
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Doni, A., Parente, R., Laface, I., Magrini, E. I., Cunha, C., Colombo, F., de Lacerda, J. F., Campos, A., Mapelli, S. N., Petroni, F., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24021-y · Cited by 66 · cited 5× · see citing works
“The improvement in mice noted by the investigators following SAP treatment was almost certainly due to the dampening effects that SAP has on cytokine secretion and attenuation of macrophage function rather than resistance to Aspergillus [18].”
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“In addition, macrophages exposed to SAP-coated C. albicans are skewed to the more tolerant M2 state, with greater secretion of anti-inflammatory cytokine IL-10 and decreased secretion of the pro-inflammatory cytokines, TNFα, IFγ, IL-6, and IL-17 [5].”
BackgroundInfluentialGilchrist, K. B., Garcia, M. C., Sobonya, R., Lipke, P. N., & Klotz, S. A. (2012) · Journal of Infectious Diseases · doi:10.1093/infdis/jis464 · Cited by 41 · cited 2× · see citing works
“This finding led us to hypothesize that SAP’s presence in deep seated fungal infections was deleterious to the host, likely dampening the host immune response [12,14,15].”
BackgroundSelf-citationA unique biofilm in human deep mycoses: fungal amyloid is bound by host serum amyloid P component
Garcia-Sherman, M. C., Lundberg, T. M., Sobonya, R., Lipke, P., & Klotz, S. (2015) · npj Biofilms and Microbiomes · doi:10.1038/npjbiofilms.2015.9 · Cited by 38 · cited 4× · see citing works
“There are few studies of the interactions of SAP with fungi other than our work [13].”
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“In addition, macrophages exposed to SAP-coated C. albicans are skewed to the more tolerant M2 state, with greater secretion of anti-inflammatory cytokine IL-10 and decreased secretion of the pro-inflammatory cytokines, TNFα, IFγ, IL-6, and IL-17 [5].”
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“This finding led us to hypothesize that SAP’s presence in deep seated fungal infections was deleterious to the host, likely dampening the host immune response [12,14,15].”
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“In addition, macrophages exposed to SAP-coated C. albicans are skewed to the more tolerant M2 state, with greater secretion of anti-inflammatory cytokine IL-10 and decreased secretion of the pro-inflammatory cytokines, TNFα, IFγ, IL-6, and IL-17 [5].”
BackgroundInfluentialInvasive candidiasis: new insights presaging new therapeutic approaches?
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“It has been suggested that miridesap treatment would hasten recovery from disseminated candidiasis, because it would increase phagocytosis and trigger a more robust immune response in a disease characterized by immune tolerance [23].”
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“Lower: Miridesap moderates the effects of SAP and allows a more balanced response including moderate pro- and anti-inflammatory cytokine secretion [16,34].”
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“Contrary to our findings it was reported that SAP opsonized Sporothrix schenkii [17].”
ResultDo Pentraxins Bind to Fungi in Invasive Human Gastrointestinal Candidiasis?
Golconda, U., Sobonya, R. E., & Klotz, S. A. (2018) · Journal of Fungi · doi:10.3390/jof4030111 · Cited by 4 · see citing works
Self-citation
Flagged first, then by citations
2 of the 34 references couldn’t be matched to a known paper.
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Cited by
Sorted by citations
Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis
Kumar, S., Song, K., Wang, J., Baghel, M. S., Zeng, Y., Shen, K., Zheng, J., Crane, J., Demehri, S., Gao, P., et al. (2025) · Nature Aging · doi:10.1038/s43587-025-00924-z · Cited by 16 · see citing works
“This compound efficiently binds to SAP, leading to the dissociation of SAP from bound amyloids and subsequent depletion of SAP levels in the body 24,62–68 .”
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“Thus, in this mouse model of disseminated candidiasis, SAP injections early in the infectious process ameliorated disease [12].”
InfluentialSelf-citation
- Authors
- Klotz, S. A., & Lipke, P. N.
- Affiliations
- University of Arizona (US)
- Brooklyn College (US)
- Corresponding author
- Klotz, Stephen A.
- Venue
- Pathogens
- Publisher
- MDPI AG
- Published
- 2022-11-06
- Volume
- 11
- Issue
- 11
- Pages
- 1304
- ISSN
- 2076-0817 (ISSN-L)
- PMC
- PMC9697064
- OpenAlex
- W4308440488
- Cited by
- 5
- References
- 34
- Citations by year
- 2025: 2 · 2023: 3
- FWCI
- 0.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Pathogens (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UA Campus Repository (The University of Arizona) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- serum amyloid P component, systemic candidiasis, Candida albicans, pentraxins, C-reactive protein, functional amyloids, macrophage polarization, M1/M2 macrophages, host immune response, cytokine production, mouse model
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