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. 2019 Jul 23;87(8):e00348-19.
doi: 10.1128/IAI.00348-19. Print 2019 Aug.

Spectrum of Trained Innate Immunity Induced by Low-Virulence Candida Species against Lethal Polymicrobial Intra-abdominal Infection

Elizabeth A Lilly  1 , Junko Yano  1 , Shannon K Esher  1 , Emily Hardie  1 , Paul L Fidel Jr #  2 , Mairi C Noverr #  1
Affiliations

Spectrum of Trained Innate Immunity Induced by Low-Virulence Candida Species against Lethal Polymicrobial Intra-abdominal Infection

Elizabeth A Lilly et al. Infect Immun. .

Abstract

Polymicrobial intra-abdominal infections (IAI) are clinically prevalent and cause significant morbidity and mortality, especially those involving fungi. Our laboratory developed a mouse model of polymicrobial IAI and demonstrated that coinfection with Candida albicans and Staphylococcus aureus (C. albicans/S. aureus) results in 80 to 90% mortality in 48 to 72 h due to robust local and systemic inflammation. Surprisingly, inoculation with Candida dubliniensis and S. aureus resulted in minimal mortality, and rechallenge of mice with lethal C. albicans/S. aureus conferred >90% protection up to 60 days postinoculation. Protection was mediated by Gr-1+ polymorphonuclear leukocytes, indicating a novel form of trained innate immunity (TII). The purpose of this study was to determine the microbial requirements and spectrum of innate-mediated protection. In addition to Candida dubliniensis, several other low-virulence Candida species (C. glabrata, C. auris, and C. albicansefg1Δ/Δ cph1Δ/Δ) and Saccharomyces cerevisiae conferred significant protection with or without S. aureus For C. dubliniensis-mediated protection, hyphal formation was not required, with protection conferred as early as 7 days after primary challenge but not at 120 days, and also following multiple lethal C. albicans/S. aureus rechallenges. This protection also extended to a lethal intravenous (i.v.) C. albicans challenge but had no effect in the C. albicans vaginitis model. Finally, studies revealed the ability of the low-virulence Candida species that conferred protection to invade the bone marrow by 24 h post-primary challenge, with a positive correlation between femoral bone marrow fungal infiltration at 48 h and protection upon rechallenge. These results support and further extend the characterization of this novel TII in protection against lethal fungal-bacterial IAI and sepsis.

Keywords: Candida; intra-abdominal infection; polymicrobial infection; sepsis; trained innate immunity.

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Figures

FIG 1
FIG 1
Low-virulence Candida species-mediated trained innate immune protection against lethal polymicrobial IAI. Mice (n = 10/group) were given a primary i.p. challenge of C. dubliniensis strain Wü284, a C. glabrata clinical isolate, C. auris strain AR0386, C. albicans efg1Δ/Δ cph1Δ/Δ (DAY185 background), or S. cerevisiae strain FY4 in combination with S. aureus strain NRS383 (A) or alone (B), followed by a lethal challenge of C. albicans/S. aureus (Ca/Sa) after 14 days. Animals receiving no primary challenge served as the positive (lethal) control. Mice were monitored for 10 days post-lethal challenge. Data are cumulative of three separate experiments. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001 (for values significantly different from those of the control, by log rank Mantel-Cox test).
FIG 2
FIG 2
Role of hyphae in C. dubliniensis-mediated trained innate immune protection against lethal polymicrobial IAI. Mice (n = 10/group) were given a primary i.p. challenge of wild-type C. dubliniensis Wü284, the nrg1Δ/Δ mutant strain, the nrg1Δ/Δ NRG1 reintegrant strain, the tlo1Δ/Δ tlo2Δ/Δ (tloΔΔ) double-null mutant strain, or corresponding reintegrant strain (tloΔΔ TLO1 or tloΔΔ TLO2 strain), followed by C. albicans/S. aureus lethal challenge after 14 days. Animals receiving no primary challenge served as the positive (lethal) control. Mice were monitored for 10 days post-lethal challenge. Data are cumulative of two separate experiments. **, P < 0.01; ***, P < 0.001; ****, P < 0.0001 (for values significantly different from those of the control, by log rank Mantel-Cox test). H+, hyphae; Y+, yeast only.
FIG 3
FIG 3
Trained innate immune protection following multiple lethal challenges. Mice (n = 10/group) were given a primary i.p. challenge of C. dubliniensis (Cd) followed by a single C. albicans/S. aureus (Ca/Cs) lethal challenge after 14 days or by two consecutive lethal challenges separated by 20 days (for those that survived the first lethal challenge). Animals receiving no primary challenge served as the positive (lethal) control. Each group was observed for morbidity and mortality for 10 days after the final lethal challenge. Data are cumulative of two separate experiments. **, P < 0.01 (for values significantly different from those of the control, by log rank Mantel-Cox test).
FIG 4
FIG 4
Longevity of protection. Mice (n = 10/group) were given a primary i.p. challenge of C. dubliniensis 7, 14, or 120 days prior to C. albicans/S. aureus lethal challenge. Animals receiving no primary challenge served as the positive (lethal) control. Mice were monitored for 10 days post-lethal challenge. Data are cumulative of two separate experiments. ***, P < 0.001; ****, P < 0.0001 (for values significantly different from those of the control, by log rank Mantel-Cox test).
FIG 5
FIG 5
Other models of infection. Mice (n = 5 to 10/group) were given a primary i.p. challenge of C. dubliniensis (Cd) followed by a lethal C. albicans (Ca) intravenous challenge (1 × 105 cells/mouse) and observed for morbidity and mortality for 10 days (A) or by a vaginal challenge of C. albicans 3153A (1 × 103), NUM51 (5 × 104), or DAY185 (5 × 105) and assessed for vaginal fungal burden on days 2, 4, and 7 (expressed as the number of CFU/100 μl vaginal lavage fluid [VLF]) (B). Animals receiving no primary challenge served as the positive control. Data are cumulative of two separate experiments. ****, P < 0.0001 (for values significantly different from those of the control, by log rank Mantel-Cox test).
FIG 6
FIG 6
Bone marrow infiltration following primary challenge. (A) Mice (n = 2/group) were sacrificed at 24 or 48 h following challenge with C. dubliniensis, C. glabrata, C. auris, C. albicans efg1Δ/Δ cph1Δ/Δ, S. cerevisiae, or a sublethal inoculum of C. albicans, and femoral bone marrow was isolated and assessed for fungal burden. Results are expressed as the number of CFU/ml of bone marrow cell suspension. Percentages above each set of bars represent protection conferred by each fungal strain upon C. albicans/S. aureus lethal challenge. (B) Correlation (regression analysis) between fungal infiltration into femoral bone marrow at 48 h and the average level of protection recorded for each species in other experiments.
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