Advances in our understanding of the pathogenesis of infectious meningitis

promotion. Science 227:375-381, 1985. Duee ED, Vignais PV: Exchange between extra- and intra-mitochondrial adenine nucleotides. Biochem Biophys Acta 107:184-188, 1965. Ellefson RD: Porphyrinogens, porphyrins, and the porphyrias. Mayo Clinic Proceedings 57:454-458, 1982. Frenkel K: Carcinogen-mediated oxidant formation and oxidative DNA damage. Pharmacologics and Therapeutics 53:127-166, 1992. Gaydos CA, Summersgill JT, Sahney NN, Ramirez JA, Quinn TC: Replication of Chlamydia pneumoniae in vitro in human macrophages, endothelial cells, and aortic smooth muscle cells. Infect Immun 64:1614-1620, 1996. Gajdos A: Excess porphyrin formation following administration of inhibitors of the biosynthesis of ATP Acta Med Stand 446:35-40,1966. Gibson JB, Goldberg A: The neuropathology of acute porphyria. J Path Bacterial 71:495-509, 1956. Gill SD, Stewart RB: Respiration of L cells infected with Chlamydia psittaci. Canadian J Microb 16:1033-1039, 1970. Hatch TP, Al-Hossainy E, Silverman JA: Adenine nucleotide and lysine transport in Chlamydia psittaci. J Bacterial, 150:662-670, 1985. Hindmarsh JT The porphyrias: recent advances. Clin Chem 32:1255-1263,1986. Horoschak KD, Moulder JW: Division of single host cells after infection with chlamydiae. Infect Immun 19:281-286, 1978. Kalckar HM: 50 years of biological research - from oxidative phosphorylation to energy transport regulation. Annual Rev Biochem 60: l-37, 199 1. Kauppinen R, Mustajoki P: Acute hepatic

Advances in Our Understanding Nariner K. Midha, M.S., M.(A.S.C.P.)S.M.,D.L.M. Assistant Director Clinical Microbiology Laboratory Department of Pathology Vanderbilt University Medical Center Nashville, Tennessee 37232

Introduction Meningitis can be defined as inflammation of the meningesthat is identified by an abnormal number of white blood cells (WBCs) in the cerebrospinalfluid

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induction of Atlas activity in elementary bodies. Infect Immun 57:3338-3344,1989. Pedersen PI, Carafoli E: Ion motive ATPases. II. Energy coupling and work output. Trends Biochem Sci 12:145-150, 1987. Pedersen PI, Carafoli E: Ion motive ATPases. I. Ubiquity, properties, and significance to cell function. Trends Biochem Sci 12:145-150, 1987. Penefsky HS, Cross RL: Structure and mechanism of F,F,-type ATP synthases and ATPases. Advanced Enzymology and Related Areas in Molecular Biology. 64:173-214, 1991. Senior AE: ATP synthesis by oxidative phosphorylation. Physiol Rev 68: 177231, 1988. Slater EC: The mechanism of the conservation of energy of biological oxidation. Eur J Biochem 166:489-504, 1987. Weiss E: Adenosine triphosphate and other requirements for the utilization of glucose by agents of the psittacosistrachoma group. J Bacterial 90:243-253, 1965. Weiss E, Kiesow LA: Incomplete citric acid cycle in agents of the psittacosistrachoma group. Bacteriology Proceedings 85, 1966. Weiss E, Myers W, Dressler HR, ChunHoon H: Glycose metabolism by agents of the psittacosis-trachoma group. Virology 22:551-562, 1964. Weiss E, Wilson NN: Role of exogenous adenosine triphosphate in catabolic and synthetic activities of Chlamydia psittaci. J Bacterial 97:719-724, 1969. Yeung Laiwah AA, Rapeport WG, Thomson GG, Machee GJA, Philip MF, Moore MR, Brodie MJ, Goldberg A: Carbamazepine-induced non-hereditary acute porphyria. Lancet i:790-792, 1983.

porhyria and hepatocellular carcinoma. Br J Cancer 57: 117-120, 1988. Kordac V: Frequency of occurrence of hepatocellular carcinoma in patients with porphyria cutanea tarda in long-term follow-up. Neoplasma 19:135-139, 1972. Koul S, Singh J, Dhingra PN, Kharta GS: Studies on experimental mastitis in goat histoenzymology. Comparative Immunology and Microbiology of Infectious Diseases. 16:307-316, 1993. Lehninger AL: The Mitochondrion: Molecular Basis of Structure and Function. The Benjamin Company, Inc., New York, 1990. McClarity G: Chlamydiae and the biochemistry of intracellular parasitism. Microbial 2:157-164, 1994. Meola T, Lim HW: The porphyrias. Bullous Diseases 11:583-596, 1993. Moore MR: Biochemistry of porphyria. Int J Biochem 1993, 10:1353-1368. Moulder JW, Grisso DL, Brubaker RR: Enzymes of glucose catabolism in a member of the psittacosis group. J Bacterial 89: 810812, 1965. Mustajoki P, Tenhunen R: Variant of acute intermittent porphyria with normal erythrocyte uroporphyrinogen-I-synthase activity. Eur J Clin Invest 15:281-284, 1985. Ong G, Thomas BJ, Mansfield AO, Davidson BR, Taylor-Robinson: Detection and widespread distribution of Chlamydia pneumoniae in the vascular system and its possible implications. J Clin Path 49:102-106, 1996. Ormsbee RA, Weiss E: Trachoma agent: glucose utilization by purified suspensions. Science 1963, 142:1077-1078. Peeling RA, Peeling J, Brunham RC: High-resolution 3’P nuclear magnetic resonance study of Chlamydia trachomatis:

of the Pathogenesis of Infectious Meningitis

(CSF). Infectiousmeningitisis simply the invasion of and replication within the meningesand CSF by microorganisms. There have beenconsiderableadvances in our understandingof the pathogenesis of infectious meningitis. It is the purposeof this brief report to review these advances.Anatomically, the blood-brain barrier is a critical element in the pathogenesisof central nervoussystem(CNS) infections and can be divided into bloodCSF and blood-brain barriers.For infectious meningitis, it is the choroid plexus

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andthe arachnoidmembranethat are now thought to be key factors in pathogenesis. The anatomy of thesestructuresis briefly reviewed,

Pertinent Anatomy the Meninges

of

The human brain is suspendedwithin a cerebrospinalfluid-filled spacewhich acts asa shock absorberto isolate the relatively delicate brain from traumatic events. The CSF is contained within the meningesof which there are three layers

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surrounding the brain. The inner layer of meninges closest to the brain is the pia mater which is contiguous with the external surface of the brain. The middle layer of meninges is the arachnoid which encloses the brain more loosely. Together the pia mater and arachnoid are known as the leptomeninges. The outer layer of the meninges is the dura mater which is mostly adherent to the periosteum and skull. Between the pia mater and the arachnoid space is the CSF-filled subarachnoid space which surrounds and cushions the brain. The outward pressure of CSF holds the arachnoid layer of meninges in contact with the dura mater. The CSF is produced mainly by the choroid plexus which is located within the lateral, third, and fourth ventricles.

Pathogenesis

of Infection

Most types of infectious meningitis appear to share a similar pathogenesis. The first step is often colonization of mucous membranes. Microorganisms that can adhere to mucosal epithelium with fimbriae (pili) as well as evade destruction by white blood cells due to an antiphagocytic capsule are often important causes of meningitis. These etiological agents appear to attach to gag receptors on mucous membranes of the nasopharynx and oropharynx using attachment sites on fimbriae that are molecular mimics of heparin sulfate. In order to reach the blood stream, microorganisms also need to cross the mucosal epithelium and then work their way through the basement membrane. After colonization of the initial mucosal site, microorganisms invade epithelial cells or cross mucosal tissue into the lymphatics or the bloodstream where they then disseminate throughout the vascular system creating a bacteremic or viremic phase. Invasion into the bloodstream by Hemophilus influenzae colonizing the nasopharynx,for example, can be accomplishedby direct invasion of epithelial cells or can be accomplished by this microorganism’sability to pass between the junctions of epithelial cells. The capability of pathogensto cross basementmembraneis obviously a factor; surface-boundplasmin activity may enhancethis ability. It is relatively easy for microorganismsto invade mucosaltissueand enter the blood streamthrough local capillar-

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ies or lymphatics. This is becausecapillaries throughout the vascular system, with the exception of thosein the brain, are fenestratedand thus allow large molecules,cells, and even microorganismsto passbetween the adjacent endothelial cells. In addition, most capillary endothelial cells have an active pinocytotic vesicular transport system and few mitochondria. In contrast, cerebral capillaries (except those of the pituitary gland, the choroid plexuses, and severalstructuresin the brain stem) have tight junctions known as zonulae occludensthat prevent intercellular transport. Moreover, cerebral capillaries have rare or absentpinocytotic vesicles and abundantmitochondria, the exact oppositeof other capillaries. It would be predicted that passageof microorganismsthrough the blood-CSF capillary barrier would be more difficult than through other blood-tissuecapillary barriers. Recent studies, however, have shown that pathogenic microorganisms attach and are then internalized at the apical side of brain endothelial cells and transportedinside intracellular vacuoles to the basolateralside, where they are exocytosedinto the basementmembrane. Plasmin, bound to the microorganism by S and type 1 fimbrae, then degrades the laminin network of the basement membraneand allows penetration. After the microorganism enters the CSF through the blood-brain barrier through invasion of brain endothelial cells, loss of capillary integrity, or through some other mechanism(s),it is able to replicate within the meningesand CSF. It is the presenceof the microorganismin the CSF that facilitates the laboratory diagnosisof meningitis. The CNS hasno lymphatic system. The only place in the brain where lymphatics are found is within the spinal epidural space.Under experimental conditions, certain viruseshave been shownto enter the subarachnoidspace from lymphatics within peripheral nerves. Moreover, viruses have also beenshownexperimentally to reproduce in Schwann cells surroundingperipheral nervesand to ascendwithin thesenerves at a rate equal to reverse axoplasma flow. Such experimental infection of the central nervous systemby neurotropic spreadof viruses hasreceived a great deal of interest, but to date haslittle known clinical importance except for

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rabies and herpesviruses.

Summary As can be seenby the above discussion, the pathogenesisof infectious meningitis is now much better understoodand considerably more complicated than appreciated in the past. Advances in our understandingof the pathogenesisof any infection are often followed by advancesin prevention and/or therapy. Let us hope this is the casefor infectious meningitis.

Bibliography Ashwal S, Tomasi L, Schneider S et al.: Bacterial meningitis in children: pathophysiology and treatment. Neurology 42:739-748, 1992. Elsinghorst EA, Weitz JA: Epithelial cell invasion and adherence directed by the enterotoxic Escherichiu coli tib locus is associated with a 104-kilodalton outer membrane protein. Infect Immun 62:3463-3471, 1994. Huang S-H, Wass C, Fu Q, Prasadarao NV, Stins M, Kim KS: Escherichiu coli invasion of brain microvascular endothelial cells in vitro andin vivo: molecular cloning and characterization of invasion gene ibel0. Infect Immun 6344704475, 1995. Korhonen TK, Virkola R, Lahteenmlki K, Bjorkman Y, et al.: Penetration of fimbriate enteric bacteria through basement membranes: a hypothesis. FEMS Microbial Lett 100:307-312, 1992. Meier C, Oelschlaeger TA, Merkert H, Korhonen TK, Hacker J: Ability of Escherichiu coli isolates that cause meningitis in newborns to invade epithelial and endothelial cells. Infect Immun 1996. Moser R, Schleiffenbaum B, Grosurth Pet al.: Interleukin 1 and tumor necrosis factor stimulate human vascular endothelial cells to promote transendothelial neutrophi1 passage. J Clin Invest 83:444-455, 1989. Parkkinen J, Hacker J, Korhonen TK: Enhancement of tissue plasminogen activated-catalyzed plasminogen activation by Escherichia coli S fimbriae associated with neonatal septicaemia and meningitis. Thromb Haemostasis 65:483-486, 1991. Quagliarello V, Scheld WM: Bacterial meningitis: pathogenesis, pathophysiology, and progress. N Engl J Med. 327:864-872, 1992. Rappaport SI: The Blood-Brain Barrier in Physiology and Medicine. New York: Raven Press, 1976. Saez-Llorens X, Ramilo 0, Mustafa MM, et al.:

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Molecular pathophysiology of bacterial meningitis: current concept and therapeutic implications. J Pediatr 116:671-684, 1990. Sande MA, Tauber MG, Scheld WM et al.: Pathophysiology of bacterial meningitis: summary of the workshop. Pediatr Infect Dis J 8:929-933, 1989. Scheld WM, Whitley RJ, Durack DT, eds.: Infections of the Central Nervous System. New York: Raven Press, 1991. Schleimer RP, Rutledge BK: Cultured human vascular endothelial cells acquire adhesiveness for neutrophils after stimulation with interleukin 1, endotoxin and tumor promoting phorbol diesters. J Immunol 136649-654, 1986. Stehbens WE: Anatomy of the blood vessels

of the brain and spinal cord. In: Stehbens WE ed. Pathology of the Cerebral Blood Vessels. St Louis: CV Mosby, l-59, 1972. St. Geme JW, Falkow S: Haemophilus infuenzae adheres to and enters cultured human epithelial cells. Infect Immun 58:4036-4044, 1990. Stephens DS, Farley MM: Pathogenic events during infections of the human nasopharynx with Neisseria meningitidis and Haemophilus influenzae. Rev Infect Dis 13:22-33, 1991. Truax RC, Carpenter MB: Human Neuroanatomy. 6th ed. Baltimore: Williams & Wilkens, 80, 1969. Tunkel AR, Scheld WM: Pathogenesis and pathophysiology of bacterial meningitis. Clin Microbial Rev 1993,6: 118-136.

Aimsand Scope

Editor-in-Chief Charles W. Stratton, MD Vanderbilt University School of Medicine Nashville. Tennessee

Antimicrobics and Infectious Diseases Newsletter (AIN) provides a simple way to keep posted on current and anticipated changes in regulatory standards and guidelines for antimicrobial agents. Each month&e latest on new drugs and in vitro diagnostics will be rcponed in AIN. Additionally, AIN will provide the reader with concise updates that address current questions in diagnosis and treatment of infectious disease. Comprehensive articles will deal with the pros and cons of proven and developing treatments for infectious disease. Intriguing case reports and editorial comments on controversies in antimicrobic research and infectious disease will be regular features of this refurbished newsletter.

General

Information

Antimicrobics and Infectious Diseases Newsletter is published monthly by Elsevier Science Inc. Subscription information can be found inside the front cover. This newsletter has been registered with the Copyright Clearance Center, Inc. Consent is given for copying articles for personal or internal use, or for the personal or internal use of specific clients. This consent is given on the condition that the copier pay through the Center the per-page fee stated in the code on the first page for copying beyond that permitted by the US Copyright Law. If no code appears on an article, the author has not given broad consent to copy, and permission to copy most be obtained directly from the author. This consent does not extend to other kinds of copying, such as for general distribution, resale, advertising and promotional purposes, or for creating new collective works. Address orders, changes of address, and claims for missing issues to Journal Fulfillment Department, Elsevier Science Inc., 655 Avenue of the Americas, New York, NY 10010. Claims for missing issues can bc honored only up to three months for domestic addresses and six months for foreign addresses. Duplicate copies will not bc sent to replace ones undelivered due to failure to notify Elsevier of change of address. Postmaster: Send address changes to Antimicrobics and Infectious Diseases Newsletter, Elsevier Science Inc., 655 Avenue of the Americas, New York, NY 10010. Address editorial correspondence to Charles W. Stratton, MD. Director of Clinical Microbiology, Depanmcnt of Pathology, Vanderbilt University Medical Center, Room 4525-TVC. The Vanderbilt Clinic, Nashville, TN 37232. e-mail: [email protected]

Tunkel AR, Wispelwey B, Scheld WM: Bacterial meningitis: recent advances in pathophysiology and treatment. Ann Intern Med 112:610-623,199O. Tunkel AR, Wispelwey B, Scheld WM: Pathogensis and pathophysiology of meningitis. Infect Dis Clin North Am 4555-581, 1990. Waggener JD: The pathophysiology of bacterial meningitis and cerebral abscesses: an anatomical interpretation. Adv Neurol 6:1, 1974. Wispelwey B, Lesse AJ, Hansen E et al.: Haemophilus hjluenzae lipopolysaccharideinduced blood brain barrier permeability during experimental meningitis in the rat. J Clin Invest 82:1339-1346, 1988.

International Editors Roger G. Finch, FRCP, FRC Path, FFPM Nottingham, United Kingdom

Dana Milatovic, MD Munich, Germany

Ricardo A. Durlach, MD Buenos Aires, Argentina

Robert Skov, MD Copenhagen, Denmark

Senior Editors Daniel Amsterdam, PhD Buffalo, New York

Jerome J. Schentag, PharmD Buffalo, New York

Burke A. Cunha, MD Mineola, New York

John T. Sinnott, MD Tampa, Florida

H. Bradford Hawley, MD Dayton, Ohio

Clyde Thomesbeny, PhD Franklin, Tennessee

Richard F. Jacobs, MD Little Rock, Arkansas

Roger L. White, PharmD Charleston, South Carolina

Ronald N. Jones, MD Iowa CiQ, Iowa Associate Editors John S. Czachor, MD Dayton, Ohio

Sally H. Houston, MD Tampa, Florida

Allen H. Graves, MD Opelika, Alabama

Thomas F. Patterson, MD San Antonio, Texas

John N. Greene, MD Tampa, Florida

Jan Patterson, MD San Antonio, Texas

Will Harley, MD Charlotte, North Carolina

Michael Towns, MD Rome, Georgia

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