CNS Macrophages and Infant Infections

Abstract

The central nervous system (CNS) harbors its own immune system composed of microglia in the parenchyma and CNS-associated macrophages (CAMs) in the perivascular space, leptomeninges, dura mater, and choroid plexus. Recent advances in understanding the CNS resident immune cells gave new insights into development, maturation and function of its immune guard. Microglia and CAMs undergo essential steps of differentiation and maturation triggered by environmental factors as well as intrinsic transcriptional programs throughout embryonic and postnatal development. These shaping steps allow the macrophages to adapt to their specific physiological function as first line of defense of the CNS and its interfaces. During infancy, the CNS might be targeted by a plethora of different pathogens which can cause severe tissue damage with potentially long reaching defects. Therefore, an efficient immune response of infant CNS macrophages is required even at these early stages to clear the infections but may also lead to detrimental consequences for the developing CNS. Here, we highlight the recent knowledge of the infant CNS immune system during embryonic and postnatal infections and the consequences for the developing CNS.

Keywords: CNS-associated macrophages; TORCH; maternal immune activation; microglia; postnatal infections; prenatal infections.

Figure 1

Consequences of early CNS infections and peripheral immune activation for CNS development. Illustration of prenatal and postnatal infections and indirect effects of maternal immune activation (MIA) on the fetus. Different viral, bacterial and parasitic infections can endanger the correct development of the CNS of the fetus leading to a plethora of symptoms grouped under the name “TORCH” syndrome. Also, maternal infection without the transmission of the pathogen to the fetus can have detrimental effects on CNS development which have robustly been linked to schizophrenia and autism spectrum disorder (ASD). Birth and the accompanying contact to environmental pathogens pose a great threat to the unchallenged immune system of the newborn in the worst cases leading to bacterial sepsis, viral encephalitis, and systemic candidiasis.

Figure 2

Infections of the prenatal CNS. (a) Illustration of the healthy central nervous system (CNS) including the vasculature, the perivascular space, and the brain parenchyma. (b) A typical ZIKV infection mostly affecting CNS macrophages inducing neuronal progenitor cell (NPC) apoptosis and recruiting peripheral monocytes and neutrophils to the site of infection via various cytokines and chemokines. The blood-brain barrier (BBB) integrity is compromised in this process. Microgliosis, astrogliosis and microglia nodules around NPC bodies are often observed. (c) A typical parasitic CNS infection by Toxoplasma gondii is shown. The pathogen gains access to the CNS with the help of circulating monocytes, carrying the parasite to through the compromised BBB, also known as a “Troian horse” infection. This causes microglia nodules, abundant cytokine release by microglia and CNS-associated macrophages (CAMs), and subsequent infiltration by monocytes and granulocytes.

Figure 3

Infections of the neonatal CNS. (a) Illustration of the healthy CNS including the vasculature, the perivascular space, and the brain parenchyma. (b) Group B streptococcus (GBS) infection. GBS enters the CNS either paracellularly, via transcytosis or exploiting trafficking phagocytic host cells. This leads to the secretion of inflammatory cytokines by resident macrophages in the perivascular space and meninges. As GBS spreads more into the CNS this inflammatory response is also mounted by endothelial cells and microglia, leading to leakage of the BBB and therefore an increase number of monocytes and neutrophils in the CNS. (c) HIV infection. HIV infects CD4⁺ T cells, monocytes, and macrophages. Infection of circulating monocytes helps HIV to enter the CNS where it infects other tissue-resident macrophages. This leads to an acute immune response with secretion of proinflammatory cytokines. (d) Candida albicans infection. Candida albicans enters the CNS either para- or intracellularly or shuttled inside circulating monocytes. Infection of the CNS leads to an activation of microglia, astrocytes, and oligodendrocytes resulting in the secretion of cytokines and chemokines and subsequently to the recruitment of neutrophils and other circulating monocytes.