Table 1.

Pathogenesis and host responses elicited during a prototype bacterial (Streptococcus pneumoniae) or viral (lymphocytic choriomeningitis virus) infection of adult hosts when localized in either the periphery or the CNS [data adapted from Ref. (10–15)]^a.

	Streptococcus pneumoniae		Lymphocytic choriomeningitis virus
	Pneumonia	Meningitis	Visceral infection (liver, spleen)	Meningitis
Natural routes of infection (humans)	Inhalation Local spread from nasopharyngeal colonization	Inhalation Local spread from an infected sinus or inner ear	Inhalation	Inhalation
			Direct contact with infected rodents	Direct contact with infected rodents
			Direct inoculation via infected solid organ transplant	Direct inoculation via infected solid organ transplant
Experimental routes of infection (mice)	Intranasal	Intranasal	Intravenous	Intracranial
		Intracisternal	Intraperitoneal
Innate immune receptors activated	TLR2, TLR4, TLR9, NOD2, NRLP3	Unknown	TLR2, PKR, RLR, TLR7, MDA5	TLR2, CXCR3
Early innate immune mediators induced	IL-1β, TNF-α, IL-6	IL-1β, TNF-α, IL-6	IFN-α/β, TNF-α, IL-6, IL-10, CCL2, CCL5, CXCL10	IFN-α/β, CCL2, CCL3, CCL5, CXCL10
Site of main adaptive immune priming	Hilar/mediastinal lymph nodes	Cervical lymph nodes	Spleen	Spleen
	Spleen	Spleen	Mesenteric lymph nodes	Cervical lymph nodes
Principal effector cells activated and mobilized	Neutrophils	Neutrophils	CD8+ CTL	CD8+ CTL Monocytes
	Monocytes	Monocytes	NK cells
	Dendritic cells	Dendritic cells	Dendritic cells
	Lymphocytes	Lymphocytes
Time to mobilize immune cells to target tissue	Hours	Hours	Hours–days	Hours–days
Soluble immune mediators involved in pathogen containment and/or clearance	IL-1β, TNF-α, NO, complement C1, IL-10	TNF-α, ROS, NO	IFN-α/β	IFN-α/β, CXCL10, IFN-γ
Mechanisms of pathogen clearance	Phagocytosis	Phagocytosis	Virus-specific CTL	Virus-specific CTL
	Neutrophil oxidative burst	Neutrophil oxidative burst
	Complement activation	Complement activation
Other relevant immune features	Disease severity and complications higher in asplenic individuals (humans)	Intracranial complications more common in asplenic individuals (humans)	Vicerotropic viral strains may cause chronic infection and immunosuppression via CTL exhaustion (mice)	No evidence of chronic CNS infection (humans)
	IκB and IL-10 polymorphisms raise susceptibility (humans)
Potential for target tissue immunopathology (humans)	Moderate (10% overall mortality)	High (75% develop intracranial complications, 25% mortality)	Low (healthy adults)	Low (healthy adults)
			High (immunocompromised organ transplant recipients)	High (immunocompromised organ transplant recipients)
Potential for target tissue immunopathology (Mice)	High (most models cause lethal disease with extensive lung damage)	High	Moderate (adult mice)	High (adult mice infected with naturally occurring Armstrong strain)
Effectors of target tissue immunopathology	Lipocalin-2, NO, malondialdehyde, IL-1β, TNF-α	IFN-γ, TNF-α, glutamate, NO, ROS, caspase-9/3, myeloperoxidase	Virus-specific CTL, perforin	Virus-specific CTL, perforin
Role of immunotherapy in improved disease outcome	No proven role to date (humans)IVIG, MALP-2, and pneumococcal P4 peptide all improve survival (mice)	Corticosteroids of limited benefit to prevent hearing loss (humans)	No proven role to date (humans)	No proven role to date (humans)Virus-specific CTL plus virus-specific CD4+ T cells can clear persistent infection following adoptive transfer (mice)
		Inhibitors of caspases, ROS, IDO, kynurenine pathway improve cognitive outcomes (mice)

^aIncludes studies where peripheral and CNS responses were not directly compared, and therefore differences may reflect how the individual studies were conducted and what parameters were examined.

CCL, C–C motif ligand; CTL, cytotoxic T lymphocyte; CXCL, C–X–C motif ligand; CXCR, C–X–C motif receptor; IDO, indoleamine 2,3-dioxygenase; IFN, interferon; IL, interleukin; IVIG, intravenous immune globulin; MALP, macrophage-activating lipopeptide; MDA, melanoma differentiation-associated protein; NO, nitric oxide; NOD, nucleotide-binding oligomerization domain-containing protein; NRLP, NOD-like receptor family, pyrin domain-containing; PKR, protein kinase R; RLR, RIG-I-like receptor; ROS, reactive oxygen species; TLR, Toll-like receptor; TNF, tumor necrosis factor.