CNS Mycobacteriosis



January 2017



Signalment (JPC #1492918):  A monkey


HISTORY:  This monkey developed seizures


HISTOPATHOLOGIC DESCRIPTION: Slide A:  Cerebrum:  Multifocally effacing 70% the section, affecting both gray and white matter, are multiple, well-circumscribed, coalescing granulomas up to 12 mm in diameter centered on a dense core of eosinophilic granular and basophilic karyorrhectic debris (necrosis) admixed with mineral and degenerate neutrophils.  These areas are bordered centripetally by numerous epithelioid macrophages with abundant, foamy cytoplasm and scattered multinucleated giant cells (Langhans and foreign-body type), that are further bounded by a rim of lymphocytes and plasma cells.  The inflammatory cells also infiltrate the adjacent, less affected tissue.  Adjacent to the granulomas there are also increased numbers of small caliber vessels with hypertrophied (reactive) endothelium.  Separating the granulomas there are multifocal areas of rarefaction, with loss of neuropil (necrosis), moderate numbers of foamy macrophages (gitter cells), reactive astrocytes with abundant eosinophilic cytoplasm and eccentric nuclei (gemistocytes), increased numbers of glial cells (gliosis) and edema. Though largely lost in this section, the remaining leptomeninges are mildly expanded by lymphocytes, plasma cells and macrophages.


Slide B:  Cerebrum:  Rarely, within cellular debris and multinucleated giant cells, there are few acid-fast bacilli.


MORPHOLOGIC DIAGNOSIS:  Cerebrum:  Granulomas, multifocal to coalescing, with gemistocytosis, gliosis, and rare intrahistiocytic acid-fast bacilli, monkey, non-human primate.


CAUSE:  Mycobacterium tuberculosis


ETIOLOGIC DIAGNOSIS:  Cerebral mycobacteriosis



·       Mycobacterium sp. are non-motile, gram-positive (but almost unstainable), acid-fast, non-spore forming, facultative intracellular, aerobic bacilli

·       Typical mycobacteria: M. bovis, M. tuberculosis, M. avium, M. microti

·       M. tuberculosis and M. bovis are the most common disease producing mediastinal lymphadenopathy in non-human primates and there is no apparent difference in distribution and character of the lesions produced by these two species

·       Tuberculosis is a disease acquired from humans

·       M. tuberculosis affects Old World primates more often than New World primates

·       Mycobacterium sp. most frequently cause granulomatous pneumonia and enteritis in various species; CNS manifestations are rare

·       In humans and mice, resistance to M. bovis is related to allelic variation in the natural resistance-associated macrophage protein (Nramp) genes 1 and 2



·       Transmission primarily by aerosol droplet inhalation (ingestion of infected materials can occur)

·       Virulence factors

·       Proteins – immunomodulation and protection against reactive oxygen species and reactive nitrogen intermediates

·       Cell wall components

·       Lipoarabinomannan (LAM) – prevent phagosomal maturation through transient inhibition of cytoplasmic Ca2+

·       Cord factor (dimycolyl trehalose) - surface glycolipid that inhibits chemotaxis, acts as adjuvant and is leukotoxic

·       Sulfatides - surface glycolipid containing sulfur which prevents fusion of phagosome with lysosome and interferes with reactive oxygen species

·       Mycobacteria secrete urease - inhibits acidification of phagosomes

·       Cell wall lipid lipomannan induces fusion of epitheliod macrophages, creating Langhans-type multinucleated giant cells

·       Mycobacterial components [LAM, lipomannan, phosphatidylinositol mannosides (PIMs), 19-kDa lipoprotein, trehalose dimycolate (TDM)] are recognized by pattern recognition receptors (PRR), bind and initiate proinflammatory cascades

·       M. tuberculosis enter macrophages by binding DC-SIGN via cell wall component ManLAM, with a lesser role played by CR3 and MR


·       Initial pulmonary infection:

·       M. tuberculosis enters macrophages by endocytosis mediated by several macrophage receptors:  Mannose receptors bind lipoarabinomannan, a glycolipid in the bacterial cell wall, and complement receptors bind opsonized mycobacteria

·       Once inside the macrophage, M. tuberculosis organisms replicate within the phagosome by blocking fusion of the phagosome and lysosome; M. tuberculosis blocks phagolysosome formation by inhibiting Ca2+ signals and the recruitment and assembly of the proteins that mediate phagosome-lysosome fusion 

·       Without prior sensitization bacteria proliferate in the pulmonary alveolar macrophages and airspaces during the earliest stage of primary tuberculosis (< 3-weeks), which ultimately leads to bacteremia and seeding of multiple sites


·       Development of delayed (Type IV) hypersensitivity:

·       At approximately 3-weeks after infection, a T-helper 1 (TH1) response activates macrophages to become bactericidal due to mycobacterial antigens that enter draining lymph nodes and are displayed to T cells

·       Differentiation of TH1 cells depends on IL-12, which is produced by antigen-presenting cells that have encountered the mycobacteria; M. tuberculosis makes several molecules that are ligands for TLR2, and stimulation of TLR2 by these ligands promotes production of IL-12 by dendritic cells

·       Maturation of TH1 cells, both in lymph nodes and in the lung, produce IFN-γ that ultimately aids in mycobacterial killing and the paucibacillary character of M. tuberculosis granulomas;

·       INF-γ is the critical mediator that enables macrophages to contain the M. tuberculosis infection through four key mechanisms;

·       (1) Stimulates formation of the phagolysosome in infected macrophages, exposing the bacteria to an inhospitable acidic environment

·       (2) Stimulates expression of inducible nitric oxide synthase, which produces nitric oxide, capable of destroying several mycobacterial constituents, from cell wall to DNA

·       (3) Mobilization of antimicrobial peptides (defensins)

·       (4) Stimulates autophagy to remove damaged organelles and M. tuberculosis

·       TH1 response also orchestrates the formation of granulomas and caseous necrosis; macrophages activated by IFN-γ differentiate into the “epithelioid histiocytes” that characterize the granulomatous response, and may fuse to form giant cells; this response halts the infection before significant tissue destruction or illness; in other cases the infection progresses due to advanced age or immunosuppression, and the ongoing immune response results in tissue destruction due to caseation and cavitation; activated macrophages also secrete TNF, which promotes recruitment of more monocytes

·       NK-T cells that recognize mycobacterial lipid antigens bound to CD1 on antigen-presenting cells, or T cells that express a γδ T-cell receptor, also make IFN-γ

·       TLR4, TLR9, and TLR adaptor molecule, MyD88 play important protective rolls during M. tuberculosis infection



·       Non-specific initially; followed by depression, vomition, behavioral changes, cachexia

·       Seizures

·       Occasional sudden death



·       Pulmonary:  Caseous (tuberculous) nodules in the hilar lymph nodes and lung that extend into the thoracic pleura (lesions may be cavitary)

·       Widely disseminated multifocal pinpoint to large, nodular foci of confluent, caseous granulomas to most major organs (especially spleen, kidney, liver, and various lymph nodes); cerebral mycobacteriosis may manifest as meningitis or as an intraparenchymal tuberculoma

·       Meningitis:  Granular roughening or gelatinous appearance of the meninges; rare in non-human primates

·       Granulomas may involve adjacent bone and dura



·       Focal, typical granulomas may surround a necrotic, occasionally mineralized, core

·       Lymphocytes, plasma cells and epithelioid macrophages surround the core

·       Multinucleated giant cells common at the periphery of the granuloma

·       Involved vessels exhibit obliterative endarteritis

·       In chronic lesions, fibrous, adhesive arachnoiditis develops

·       Acid fast bacilli are rarely detectable due to macrophage activation in killing M. tuberculosis as a process of granuloma formation



·       Fibrillar, electron-opaque nuclear area

·       Periphery is densely filled with ribosomes

·       Capsule in close contact with cell wall



·       Acid fast (depends on the amount and spatial arrangement of mycolic acids and their esters within the bacterial cell wall)

·       Intradermal tuberculin skin test (eyelid or abdominal skin)

·       Culture and PCR necessary for speciation



Meningitis in nonhuman primates:

·       Streptococcus pneumoniae:  Dull, thickened and opaque leptomeninges; fibrinopurulent meningoencephalitis; necrotizing vasculitis, possibly with thrombosis

·       Cytomegalovirus (CMV):  Betaherpesvirus; suppurative to nonsuppurative meningoencephalitis with necrosis and fibrinous exudates and characteristic intranuclear inclusion bodies; usually observed with SIV

·       Cryptococcus neoformans:  Common opportunistic infection 

·       Neisseria meningitides

·       Haemophilus influenza

·       Pseudomonas aeruginosa

·       Pasteurella multocida

·       Klebsiella pneumoniae

·       Listeria monocytogenes



·       Nontuberculous mycobacterial infections in nonhuman primates:

·       M. avium ss. paratuberculosis  - Johne’s disease

·       M. avium-intracellulare

·       Atypical mycobacteria:  M. marinum, M. kansasii, M. lepraemurium

·       Cattle: 

·       Pneumonia - M. bovis

·       M. avium ss. paratuberculosis - Johne’s disease

·       Horses:  Often alimentary with lesions in retropharyngeal and mesenteric lymph nodes and intestine

·       Sheep and goats:  Rare pneumonia

·       Swine:  Often systemic; M. bovis, similar lesions as in cattle;  M. avium, proliferative tuberculoid granulation tissue resembling lardaceous or sarcomatous lesions described in equine tuberculosis

·       Dog & Cat:  Discrete tuberculoid granulomas are uncommon; lesions usually appear as granulation tissue with random scattered macrophages and giant cells

·       African clawed frogs:  M. marinum;  sarcoma-like inflammatory response

·       Birds:  M. avium; CNS infection very rare; most often alimentary origin

·       Fish:  tuberculous disease caused by M. marinum - abundant in pools in regions with temperate climates; zoonotic

·       Guinea pigs: Exceptionally vulnerable to infection by as little as a few inhaled mycobacteria

·       Mice: Relatively resistant; mice do not cough or form cavitary lesions, making them a poor model for transmission studies

·       Rabbits: Most will overcome disease completely, with few culturable bacilli; model only useful in study of latent or paucibacillary disease



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2.      Brogden KA. Cytopathology of pathogenic prokaryotes. In: Cheville N, ed. Ultrastructural Pathology. 2nd ed. Ames, IA: Wiley-Blackwell; 2009:491-494.

3.      Capuano SV, Croix DA, Pawar S, et al. Experimental Mycobacterium tuberculosis infection of cynomolgus macaques closely resembles the various manifestations of human M. tuberculosis infection. Infect Immun. 2003;71(10):5831-5844.

4.      Carlton WW, Hunt RD. Bacterial diseases. In: Benirschke K, Garner FM, Jones TC, eds. Pathology of Laboratory Animals. Vol 2. New York City, NY: Springer-Verlag; 1978:1418-1427.

5.      Coscolla M, Lewin A, Metzger S, Novel Mycobacterium tuberculosis complex isolate from a wild chimpanzee. Emerg Infect Dis. 2013 Jun;19(6):969-76.

6.      Jortner BS, Percy DH. The nervous system. In: Benirschke K, Garner FM, Jones TC, eds. Pathology of Laboratory Animals. Vol 1. New York: Springer-Verlag; 1978:358-360.

7.      Magden ER, Mansfield KG, Simmons JH. Nonhuman primates. In: Fox JG, Anderson LC, Otto G, Pritchett-Corning KR, Whary MT, Fox JG, eds. Laboratory Animal Medicine, 3rd ed. San Diego, CA: Academic Press; 2015:855-857.

8.      McAdam AJ, Milner DA, Sharpe AH. Infectious diseases. In: Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia, PA: Elsevier Saunders; 2015:371-376.

9.      Sakamoto K.  The Pathology of Mycobacterium tuberculosis infection.  Vet Pathol.  2012;49:423-439.

10.   Simmons J, Gibson S. Bacterial and mycotic diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardiff S, Morris T, eds. Nonhuman Primates in Biomedical Research Volume 2: Diseases. 2nd ed. San Diego, CA: Academic Press; 2012:112-116.

11.   Valverde CR, Christe KL. Radiographic imaging of nonhuman primates. In: Wolfe-Coote, ed. The Handbook of Experimental Animals: The Laboratory Primate, 1st ed. San Diego, CA: Academic Press; 2005:373.

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