Introduction:
Meningitis is an inflammation of the meninges. The meninges consists of three membranes which encase the soft tissue of the brain and spinal cord. The layers of these membranes, from outermost to innermost are the dura mater, the arachnoid mater and the pia mater. Between the aracnoid mater and pia mater is the subarachnoid space (i.e., the space under the arachnoid matter). The subarachnoid space is filled with a clear serumlike fluid called crebrospinal fluid (CSF). The CSF provides nutrition to the CNS, while also providing a liquid cusihion for teh sensitive brain and spinal cord.
Bacterial meningitis is the leading cause of central nervous system (CNS) infection. The blood–brain barrier (BBB) protects the CNS from most bacteria that may have reached the
bloodstream. Most of the few types of bacteria, which can cross BBB to invade the meninges,
are extracellular pathogens: Escherichia coli K1 and Streptococcus agalactiae (Group B Streptococcus) in the newborn, N. meningitidis, Haemophilus influenzae type b, and Streptococcus pneumoniae in children and adults.
Bacterial meningitis is a devastating disease occurring worldwide with up to half of the survivors left with permanent neurological sequelae. Due to intrinsic properties of the meningeal pathogens and the host responses they induce, infection can cause relatively specific lesions and clinical syndromes that result from interference with the function of the affected nervous system tissue. Major pathogens include Streptococcus pneumonia, S. agalactiae (Group B Streptococcus), Neisseria meningitidis, and Escherichia coli K1, and also include a neglected zoonotic pathogen, Streptococcus suis. These neuroinvasive pathogens represent common themes of host–pathogen interactions, such as colonization and invasion of mucosal barriers, survival in the blood stream, entry into the central nervous system by translocation of the blood–brain and blood–cerebrospinal fluid barrier, and induction of meningeal inflammation, affecting pia mater, the arachnoid and subarachnoid spaces. acterial meningitis is a serious threat to global health. Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type b are most commonly associated with bacterial meningitis in infants and adults. See Doran
In sub-Saharan Africa, also called the ‘meningitis belt’, N. meningitidis is a leading cause of large epidemics of meningococcal meningitis. Further bacteria that cause meningitis in children and adults include Group B Streptococcus (GBS), Escherichia coli K1, non-typhoideal Salmonella, Klebsiella spp., Staphylococcus aureus, Listeria monocytogenes, Mycobacterium tuberculosis and the neglected porcine zoonotic pathogen Streptococcus suis. Many of the meningeal pathogens are able to colonize the skin and different mucosal surfaces of healthy individuals. In certain cases, bacteria penetrate host cellular barriers to initiate a local infection that can result in systemic spread. An association between high-level bacteremia and development of meningitis has been suggested for some bacteria. See Doran
Signs and Symptoms: include severe headache, paintul or stiff neck, fever, nausea and comiting. Early symptoms may be mistaken for flu symptoms. Phtophobia may also be noted.
Causes: Many different microrganisms can cause an infection of the meninges. Some of the more common are discussed here. Also see bacteri, viruses, parasites and fungus for further discussion of some of the microorganisms.
Neisseria meningitidis:
Introduction: Neisseria meninitidis appears as gram-negative diplococci and is commonly known as the meningococcus. The organisms causes the most serious form of acute meningitis and accounts for 15-20% of all meningitis cases. Most cases occur in young children, because vaccination of otherwise healthy children against this disease is not recommended until age 11. Because meningococci do not survive long in the environment, these bacteria are usually acquired through close contact with secretions or droplets. Meningococcal meningitis has a sporadic or epidemic incidence in late winter or early spring. The continuing reservoir of infection is humans who harbor the pathogen in the nasopharynx. The scene is set for transmission when carriers live in close quarters with nonimmune individuals, as might be expected in families, day care facilities, college dormitories and military barracks.
Structure: N. meningitidis is a fastidious, encapsulated, aerobic gram-negative diplococcus.
Colonies are positive by the oxidase test and most strains utilize maltose. The phenotypic
classification of meningococci, based on structural differences in capsular polysaccharide,
lipooligosaccharide (LOS) and outer membrane proteins, is now complemented by genome
sequence typing (ST). See Stephens
The different sialic acid (serogroups B, C, Y, and W-135) and nonsialic acid (serogroup A) capsular polysaccharides expressed by Neisseria meningitidis are major virulence factors and are used as epidemiologic markers and vaccine targets. However, the identification of meningococcal isolates with similar genetic markers but expressing different capsular polysaccharides suggests that meningococcal clones can switch the type of capsule they express. See Wenger
Although 12 different strains with different capsular antigens exist, serotypes B, C and Y are responsible for most infection in the U.S. The bacterium enters the body via the upper respiratory tract, moves into the blood, rapidly penetrates the meninges and produces symptoms of meningitis.
In gram-negative bacteria, such as N. meningitidis, the subcapsular cell envelope consists of
an outer membrane (OM), a peptidoglycan layer, and a cytoplasmic or inner membrane.
Pathogenesis/Transmission: N. meningitidis is a common inhabitant of the human nasopharynx, and as such is a normal, saprophytic organism that is transmitted from person to person by direct contact. Only in a small proportion of colonized subjects does the bacteria invade the bloodstream where they are responsible for septicemia and/or meningitis, after crossing of the blood–brain barrier.
Meningitidis can be either encapsulated or not. However, N. meningitidis strains causing
invasive disease and isolated from sterile sites such as the blood or the CSF are almost
always encapsulated. The capsule is essential for the survival of the organism in the blood as
it provides resistance to antibody/complement-mediated killing and inhibits phagocytosis. The main meningococcal capsular polysaccharides associated with invasive disease are
composed of sialic acid derivatives, except for the serogroup A capsule, which consists of
repeating units of N-acetyl-mannosamine-1-phosphate. In N. meningitidis, Nacetylneuraminic acid (Neu5Ac), unlike in mammalian cells, is synthesized from Nacetylmannosamine (ManNAc) and phospoenolpyruvate without phosphorylated intermediates. Capsular genes are located in a single locus cps within the IHT-Al 24 kb virulence island that is divided in three regions A, B, and C.
Acquisition of meningococci through exposure to respiratory secretions and attachment on
human upper respiratory mucosal surfaces by N. meningitidis are the first steps in
establishing a human carrier state and invasive meningococcal disease. Meningococcal
carriage occurs in 8–25%. The adhesive properties of capsulate N. meningitidis are
mediated by pili.
Once inside the cerebrospinal fluid (CSF), bacterial multiplication is thought to be uncontrolled, owing to the local deficiency in complement and immunoglobulins, and despite the influx of polymorphonuclear leukocytes induced by the local inflammatory response. The small number of bacterial species capable of invading the meninges suggests that specific virulence factors are required for bacteria to enter the subarachnoidal space. Among the above-mentioned extracellular bacteria, N. meningitidis is the pathogen that once in the bloodstream, is able to invade the meninges the most effectively. It has been estimated that 63% of the cases of bacteremia owing to N. meningitidis are associated with meningitis. See Nassif
Streptococcus pneumoniae: (see outline)
Streptococcus pneumoniae also referred to as pneumococcus caseus the majority of bacterial pneumonias. Meningitis is also caused by this bacterium. It is the most frequent cause of community acquired meningitis and is also very severe. About 25% of pneymococcal meningitis patients will also ahve pneumococcal pneumonia. Two vaccines are available for S. pneumoniae, Prevanar which is recommended as part of the childhood immunization schedule and Pneumovax 23, which is available for adults. Crurent recommendations for unvaccinated adults call for initial vaccination with Prevnar, followed by Pneumovax 6-12 monhts later.
Haemophilus influenzae:
The meningitis caused by this bacterium is severe. Before the vaccine was introduced in 1988, it was a very common cause of severe meningitis and death.
Listeria monocytogenes:
Introduction: Listeria monocytogenes is a gram positive bacterium that ranges in morphology from coccobacilli to long filaments in palisades formation. Listeriosis in healthy adults is often a mild or subclinical infection with nonspecific symptoms of fever, diarrhea and sore throat. However, listeriosis in elderly or immune compromised patients usually affects the brain and meninges and results in septicemia. The apparent reservoir appears to be soil and water.
Listeria monocytogenes is a saprophytic gram positive bacterium responsible for human
listeriosis, a food-borne disease characterized in immunocompromised individuals by severe
septicemia and meningoencephalitis; in pregnant women, placental infection can lead to
meningoencephalitis of the newborn and abortion.
Transmission: In humans, L. monocytogenes is transmitted by ingestion of contaminated ready to eat food products. The attack rate during outbreaks can be high, with up to 75% of affected individuals experiencing symptoms of gastrointestinal disease.
Pathology: The potential of L. monocytogenes to cause disease correlates with its capacity to survive within macrophages, to invade nonphagocytic cells and replicate therein, and also to cross the intestinal, the blood–brain, and the fetoplacental
barriers. The factors required for intracellular survival are encoded by the major virulence locus
of L. monocytogenes. They include the secreted listeriolysin O (LLO) and two phospholipases
involved in the disruption of phagosomal membranes and bacterial escape to the cytoplasm.
Studies have shown that Lm can pass through the intestinal barrier via the surface virulence factor internalin nter the bloodstream, and then transfer to the brain tissue. The central nervous system (CNS) has a specific protective barrier – the blood-brain barrier (BBB), which is composed of endothelial cells of capillary walls, astrocyte end-feet, and pericytes preventing harmful substances like toxins and pathogens from entering the brain to maintain brain homeostasis.
Studies have shown that Lm secretes listeriolysin-O (LLO) which can activate the NF-κB pathway in endothelial cells, promote the transcription of inflammatory factors such as IL-1β and TNF-α, thereby disrupting the integrity of BBB. At the same time, LLO can also induce the production of cell surface adhesion molecules P-selectin, E-selectin, intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), while the expression
of inflammatory factors such as IL-1β and TNF-α can enhance LLO-induced ICAM-1 expression, further mediating cell adhesion and promoting the entry of white blood cells into the CNS.
Treatment: Currently, antibiotics such as ampicillin, penicillin, and amoxicillin are commonly used in clinical practice to treat Lm disease. The most commonly used treatment for invasive Listeria infection is combination therapy with ampicillin and gentamicin, and the effectiveness of gentamicin combination therapy has also been preliminarily confirmed in recent clinical studies.
Although Lm is susceptible to most antibiotics, it also exhibits intrinsic resistance to certain
antimicrobial drugs. Additionally, Lm can increase its tolerance to antibiotics through stress responses such as reducing cell membrane permeability, increasing efflux pump activity, altering antibiotic structure, or changing cell components that serve as antibiotic targets.
Innate Immune Response:
Gut microbiota acts as the first line of defense against pathogenic Lm infection, playing a role in maintaining host nutrition, immunity, metabolism, and resistance to pathogens. During Lm infection, there are complex interactions between gut microbiota and the normal bacterial community. The gut microbiota can bind to receptors on the intestinal epithelial cells to block the interaction between pathogens and epithelial cells, or inhibit intestinal pathogens directly or indirectly by producing antimicrobial peptides or competing for nutrients. Lactobacillus and Bifidobacterium secrete antimicrobial peptides to inhibit the growth of Lm, while Clostridium achieves anti-infection purposes by reducing the ability of Lm to colonize the gastrointestinal tract.
–Extracellular L. monocytogenes at the cell surface:
The major failies of PRRs expressed at the cell surface are TLRs, which recognize highly conserved microbial components found in all bacteria, and C-type lcitn receptors, best known for detecting fungal cell wall components. Broad evicence for a significant role for TLR in recgonition of L. monocytogenes comes from the use of MyD88 deficient mice that lack the signaling adaptor sued by most TLR proteins. MyD88-/- mice have at least 1k fold increased bacterial burdens compared wot WT mice.
After ingestion of Lm by macrophages, Myeloid differentiation factor 88 (MyD88)-dependent response genes are activated through TLRs, thereby activating the NF-κB signaling pathway, exerting an anti-infection effect.
TLR2 is expressed on a variety of cell types, including intestinal epithelial cells and CD8+ T cells, but it is expressed at the highest level on myeloid-derived phagocytes. TLR2 binds lipoteichoic acids and liporoteins found in bacterail cell walls.
TLR5 binds flagellin, the structural subunit of bacterial flagella and is epxressed on the basolateral surface of intestinal epithelial cells.
–Cytosolic L. monocytogens:
Intracellular sensing of microbes is a critical function of the innate immune system because commensal bacteria rarely access the host cell cytosol, so detection of microbila components here typically indicates a pathogenic infection. Cytosolic PRRs that sense L. monocytogenes can be divided into two large groups: microbial cell wall components and surface proteins are detectd by NOD-like receptors (NLRs) and nucleic acids are sensed by either cyclic GMP-AMP synthetase (stimulator of interfern genes) (cylic dinucleotides), AIM2-like receptors (AT-rich double stranded DNA (dsDNA) or retinoic acid indicible gene 1 (RIG-I) like recptors (RNA).
More than 20 mmers of the NLR family have been identified to date and cytosolic L. monocytogenes can be sensed by several of these proteins. NOD1 and NOD2 both detect dipeptide components of bacterial peptidoglycan and are widely expressed by most cell types. Sensing of cytosolic L. monocytogenes by either of these receptors activates NF-kB and leads to increased transcription of proinflammaotry cheokines (e.g., CXCL2) and cytokines (e.g., IL-6, TNFalpha).
Many members of the NLR family act as scaffolds for the assembly of unique cytosolic protin complexes called inflammasomes. L. moncytogenes can be sensed by multiple inflammasomes. Although each is activated by a different stimulus, all inflammasones recruit and activate the caspases needed for either secretion of IL-1beta and IL-18 or gasdermin medaited pryoptosis, an inflammatory type of cell death.
–-Cells involved in Response:
A key function of the innate immune system druing bacterial infeciton is to trigger the release of granulocytes from the bone marrow and to direct migration of cirulating neutrophils (PMNs) to infectious foci. Sensing through either TLRs or NODs leads to NF-kB dependent expression of IL-6, CXCL2 and CXCL8 and all of these molecules act as chemoattractants for neutrophils.
–—Dendritic cells (DCs), as professional antigen presenting cells (APCs), play important roles in activating and initiating T cell immune responses in both innate and adaptive immunity. Lm, as an intracellular bacterium, primarily induces cell-mediated immunity mediated by CD8+ T lymphocytes. Post-synaptic dendritic cells (psDCs) helps CD8+ T cell responses with the assistance of CD4+ T cells.
—-Neutrophils play various roles in combating infection after being infected by Lm, including degranulation and releasing reactive oxygen species (ROS) as well as chemotaxis, activation, and phagocytosis. The response of neutrophils to Lm mostly requires the activation of Ca 2+ channels.
During infection, PMNs downregulate expression of CXCR4, a receptor that promotes retention in the bone marrow, and upregulate expression of the receptor CXCR2, which can sense the chemokines CXCL1 and CXL2. Within just 30 mintues of i.v. inoculation, cirulating PMNs genin to infiltrate the L. monocytogenes infected liver with peak numbers occuring by 4 hours posteinfection in C57BL/6 mice.
Adaptive Immune Response:
An efficient adaptive immune resposne is required to acheive sterilizing protective immunity. Activation of anive T cells in the spleen or draining lymph node requires 3 signals. A requirement for multiple signals ensures that T cells will not become activated in the absence of danger that indicates the presence of either microbes or tissue damage. Signal 1 occurs wehn an eptiope specific TCR engages with its cognate antigen (typically a papteide) that has been processed intracellular and presented on the cell surface by MNCI or MHCII proteins. Signal t, referred to as costimulation, invovles the binding of stimulatory proteins ont e surface of the T cells by ligan(s) typically expressed on professional APCs. Signal 2 costimulatory molecuels are typically upregulated only when APC are activated such as soccurs after expresoure fo MAMPs. The classic signal 2 pairing involves CD28 on the T cell and B7 (also referred to as CD80/86) on the APC. However, at least 15 other pairs of costimulatory molecules have been described. The third signal, which alter the outcome of the T cell response, depends on the local concetnraiton of type I IFN and IL-12.
–Classical MHC-I presentation:
In all nucleated cells, cytosolic proteins are cleaved into peptide lenght fragmetns (8-11 amino acids) by the proteasome and transported into the ER, where they bind newly synthesied MHC-Ia proteins and are then translocated to the cell surface. MHC-Ia proteins are normally loaded with fragments of self proteins; however, during intracellular infection, peptides derived from secreted microbial antigens are also displayed on the cell surface, and this serves as a signal to CD8+ T cells. L. monocytogenes can readily gain access to the cytosol of most cell types and thus, any proteins secreted by L. monocytogenes can potentially be processed and presented by the MHC-Ia machinery.
–MHC-II presentation:
MHC-II proteins are expressed only by APCs such as macrophages, DCs and B cells. They bind longer peptides (13-25) miano aicds derived form extracellular antigens taht are processed in degradative vacuoles, and their cell surface lelvs typially increase druing infection.
–CDR+ T cells: expansion and contration during L. monocytogenes infection closely mirrors CD8+ T cells. The peak of CD4+ T cell profliferation int he splen occurs at about the same time in mice at 6-8 days postinfection. Activated CD4+ T cells that produce IL-17A could promote bacterial clearance by inducing nuetorphil migration to sites of infection.
During the primary response to infection, a subset of effector CD8+ T cells differentiates into memory precursor effector cells that expressed hihg level so fCD127 and low levels of KLRG1.
Meningitidis caused by fugus:
Crytococcus neoformans: causes a more chronic form of meningitis with a more gadual onset of symptoms, although AIDS patients may see a fast onset. The primary ecological niche of C. neoformans is the bird population. It is prevelent in urban areas where pigeons congregate and it proliferates in the high nitrogen environment of droppings that accumulate on pigeon roosts. Systemic cryptococcsis requries immediate treatment with amphotericin B and flu conazole over a period of weeks or monthgs. There is no prevention.
Coccidioides speces: Thsi fungus causes a condition known as “Valley Fever” in the U.S. Southwest. The morphology of Coccidioides is very distinctive. at 25C it forms a moist white to brown colony with abundant, branching, septate hypahe. These hyphae fragment into thick walled, blocklike arthroconidia. There are two species that casue this disease. C immitis causes disease in California and C. posadasii casues disease in northern Mexico, Central and South American and the American Southwest, especially in Arizona. This is a true systemic fungal infection of high virulences, as opposed to an opportunistic infection. It usually beings with pulmonary infection but can disseminate quickly throughout the body. All persons inhaling the arthrospores probably develop some degree of infection, but certain groups have a enetic susceptibility that gives rise ot the more serious disease. After the arthrospores are inhaled, they develop into spherules in the lungs. These spherules release scores of endospores into the lungs.
Meningitidis caused by Viruses:
Zika Virus: Starting in 2015 an epidemic of babies born with abnormally small heads became obvious in Brazil. The cause was determiend to be the Zika virus, an RNA virus in the Flaviviridae family. It is closely related to the viruses cuasing dengue fever, West Nile fever and yellow fever. . When adults are infected with Zika, they can experience a range of symptoms, from none at all, to a skin rash, conjunctivitis and muscle and joint pina. The virus also seems to trigger Guillain-Barre syndrome in some adults which is a neurological condition that can occur after infections with certain bacteria and viruses, and soemtimes after exposure to vaccines. In late 2016, Florida started releasing genetically modified male mosquitoes near Key West. When females mate with these males, their offspring die.
Poliomyelitis (Polio): is an acute enteroviral infection of the spinal cord that can cause nuerosmusular paralysis. Because it often affects small children, it was called infantile paralysis. No civilizaiton or culture has escaped the devastation of polio. The poliovirus is in the family Picornaviridae, genus Enterovirus, named for its small size and its RNA genome. Humans are the only known reservoir. The virus is passed within the population through food, water, hands, objects contaiminated with feces and mechnaical vectors. The maintstay of polio prevention is vaccination as early in life as possible, usually in four doses starting at about 2 months of age. Adult candidates for immunization are travelers and members of the armed forces. The two forms of vaccine currently in use are inactivated poliovirus vaccine developed by Jonas Salk in 1954, and oral poliovirus vaccine developed by Albert Sabin in the 1960s. In very rate instances, the attenuated virus reverts to a neurovirulent strain taht causes disease. For this reason, IPV, using killed virus, is the only vaccine used in teh U.S.
Arboviruses: Most arthropods that serve as infectious diseases vectors feed ont he blood of hosts. Except during epidemics, detecting arboviral infections can be difficult. The patient’s history of travel to endemic areas or contact with vectors, along with serum analysis is highly supportive. Rapid seriological and nucleic acid amplification tests are availabe for some of the virsues. Arboviruses that cause encephalitis include the West Nile Virus, St. Luis Encephalitic Virus, La Crosse Virus, Powassan Virus, Jamestown Canyon Virs and Easter Equine Enecephalitis Virus.
Rabies: is a slow, progressive zoonotic disease characterized by a fatal encephalitis. Infection with rabies virus typically beings wehn an infected animal’s saliva enters a puncture site. Untreated rabies proceeds through several distinct stages that almost inevitably end in death, unless post exposure vaccination is performed before symptoms bengin. Virulence is assocaited with an envelope glycoprotein that seems to give the virus its ability to spead in the CNS and to invade certain tyeps of nueral cells. The primary reservoirs of the virus are ewidl mammals such as canines, skunks, raccoons, baders, cats and bats. Both wild and domestic mammals can spead the disease to humans through bites, scratches and inhalation of droplets. A bite from a wild or stray animal demands assessment of the animal, meticulous care of the wound and specific treatment regimen. Rabies has been transmitted to humans in the absence of a bite, aerosols of bat saliva are thought to be capable of transmitting the virus. For that reason people who have found a bat in their hosue can be encouraged to undergo the postexposure prophylaxis regimen.
Meningitidis caused by Parasites:
Naegleria fowleri: can occur in people who have been swimming in warm, natural bodies of freshwater. Infection can begin when amoebas are forced into human nasla passages as a result of swimming. Once the amoeba is inoculated intot he favorable habitat of the nasal mucosa, it burrows in, multiples and uses the olfactory nerve to migrate into the brain. Naegleria advances so rapidly that treatment usually proves futile. Studies have indicated that early therapy with amphotericin B, sulfadiazine or tetracycline in some combinations can be of some benefit. Public swimming pools and baths must be adequately chlorinated and checked periodically for the amoeba.
Acanthamoeba: This protozoan differs from Naegleria in its protal of entry. It invades broken skin, the conjunctiva and occasionally the lungs and urogenital epithelia.
Toxoplasma gondii: this protozoal infection in the fetus and in immunodeficient people, especially those with AIDS, si severe and often fatal. Although infection in otherwsie healthy people is generally unnoticed, recent data suggest that it may have subtle but profoudn effects on their brain and the responses it controls. People with a history of Toxoplasma infection are often more likely to display thrill seeking behaviors and seem to ahve slower reaction times. Most cases of toxoplasmosis are asymptomatic or marked by mild symptoms such as sore throat, lymph node enlargmenet, and lwo grade fever. T. gondi is a very successful parasite with so little host specificity that it can attack at least 200 species of birds and mammals. The parasite undergoes a sexual phase in the intestine of cats and is then released in feces, where it becomes an infective oocyte that survives in moist soil for several months. These forms eventually enter an asexual cyst state in tissues, called a pseydocyte. Humans appear to be constantly exposed to the pathogen. Many cases are caused by ingesting pseudocytes in undercooked contaminated meat and other sources include contact with other mammals or even dirt and dust contaiminated with oocysts.
Meningitidis caused by Prions:
Prions are proteinaceous infectious paricles containing no genetic material. They are known to cause diseases called transmissible spongiform encephalopathies, neurodegenerative diseases with long incubation periods but rapid progressions once they being. The human TSEs are Creutzfeldt-Jakob disease.