Maladjusted host immune responses induce experimental cerebral malaria-like pathology in a murine Borrelia and
Johan Normark1, Maria Nelson2, Patrik Engström3
1Department of Molecular Biology, Umeå University, Umeå, Sweden; Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden; Umeå Center for Microbial Research, Umeå University, Umeå, Sweden; Division of Infectious diseases, Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
Abstract:
In the Plasmodium infected host, a balance between pro- and anti-inflammatory responses is required to clear the parasites without inducing major host pathology. Clinical reports suggest that bacterial infection in conjunction with malaria aggravates disease and raises both mortality and morbidity in these patients. In this study, we investigated the immune responses in BALB/c mice, co-infected with Plasmodium berghei NK65 parasites and the relapsing fever bacterium Borrelia duttonii. In contrast to single infections, we identified in the co-infected mice a reduction of L-Arginine levels in the serum. It indicated diminished bioavailability of NO, which argued for a dysfunctional endothelium. Consistent with this, we observed increased sequestration of CD8+ cells in the brain as well over expression of ICAM-1 and VCAM by brain endothelial cells. Co-infected mice further showed an increased inflammatory response through IL-1β and TNF-α, as well as inability to down regulate the same through IL-10. In addition we found loss of synchronicity of pro- and anti-inflammatory signals seen in dendritic cells and macrophages, as well as increased numbers of regulatory T-cells. Our study shows that a situation mimicking experimental cerebral malaria (ECM) is induced in co-infected mice due to loss of timing and control over regulatory mechanisms in antigen presenting cells.
Insights
Co-infection with malaria and Borrelia duttonii impairs immune regulation, leading to reduced L-Arginine and nitric oxide bioavailability. This mimics experimental cerebral malaria, increasing inflammation and T-cell dysfunction.
Area of Science:
- Immunology
- Infectious Diseases
- Pathology
Background:
- Malaria and bacterial co-infections worsen disease severity and mortality.
- Maintaining a balance between pro- and anti-inflammatory responses is crucial for parasite clearance and preventing host pathology.
Purpose of the Study:
- To investigate immune responses in BALB/c mice co-infected with Plasmodium berghei NK65 and Borrelia duttonii.
- To understand the mechanisms underlying exacerbated disease in malaria-bacterial co-infections.
Main Methods:
- Co-infection model using BALB/c mice, Plasmodium berghei NK65, and Borrelia duttonii.
- Analysis of serum L-Arginine levels, nitric oxide bioavailability, and endothelial markers (ICAM-1, VCAM).
- Assessment of inflammatory cytokines (IL-1β, TNF-α, IL-10), immune cell populations (CD8+ T cells, regulatory T-cells), and antigen-presenting cell function.
Main Results:
- Co-infected mice exhibited reduced serum L-Arginine and diminished nitric oxide bioavailability, suggesting endothelial dysfunction.
- Increased sequestration of CD8+ T cells in the brain and overexpression of ICAM-1 and VCAM were observed.
- Elevated inflammatory cytokines (IL-1β, TNF-α) and impaired IL-10-mediated regulation were noted.
- Loss of synchronicity in immune signaling and increased regulatory T-cells were found in co-infected mice.
Conclusions:
- Co-infection with malaria and Borrelia duttonii induces a state mimicking experimental cerebral malaria.
- Dysfunctional immune regulation, particularly in antigen-presenting cells, contributes to exacerbated pathology.
- Impaired nitric oxide bioavailability and altered inflammatory responses are key features of this co-infection model.
