Gram + Bacterium just in newly cultures. Stricter anaerobic and Spore former. Pass through different phases: during bacilli phase has movement for surface fimbriaes but when he becomes a spore (racket like) lose his fimbriaes. Spore phase is ambient resistant and expectative for normal condition to become bacilli again.
Virulence
Tetanospasmina: is a toxin that has two strains: heavy chain and light chain. The heavy can be divided by tripsine in B and C. The light chain (A) mediates the disease. Initially, there is a trauma that exposes the axon to the toxin, and links to ganglioside ; after this the toxin goes to basal nucleus of neurons in CNS by retrograde transport. Once there, spread to glicinergic and GABA-ergic terminals where clives the sinaptobrevine in the pre-sinaptic membrane and blocks the neurotransmisor fusion. This inhibition elicits an elevated stimulation by normal nervous ways that express like augmentation of muscle contraction. And the spasms is produced by incapability of inhibition afferent stimuli. These inhibitory neurons also control catecholamine release by suprarenal gland which reflects like sympathetic tone elevation.
Adhesion: Fibronectine-binding protein, int-A like protein Hemolysin Tetanolisine: Lyses of cholesterol membrane cells. Collagenase: Permits interstitial spread. Note: an infected person is not contagious, the transmission only occurs with spores present on the ambient.
Pathology
Exists four disease’s presentation ways: generalized, localized, cephalic and natal.
Generalized: Trismus, sardonic laugh, abdominal rigidity, generalized spasms (opistotonos) with conscience conservation but pain.
Gram + bacterium, catalase +, and becomes a group like chinese stick’s. In their cytoplasm there are meta-chromatic granules. This bacterium doesn’t have capsule, movement or spore form. There three types: Gravis, mitis, intermediate and belifante. Normally, a phage infects the cell and integrates the tox+ gene with exotoxin information. This exotoxin goes to bacteria genoma and replicates, after that exotoxin is released to the host cells.
Virulence
Diphteric Toxin: A-B type toxin which B binds to epithelial cells, after is endocytosed and leave the endosome when the Ph is higher. The A portion lick the elongation factor 2 and stops protein synthesis. This toxin is very immunogenic and constitutes the diphtheria vaccine.
Adhesion: Hemaglutinins and fimbriae links to the macrophages via lecithin. Bacterium has a receptor for: N-acetyl glucosamine, N-acetyl galactosamine, galactose, manose, sialic acid. Also has hydrophilic and hydrophobic protein which creates an hydrophobic contact. Lastly, neuroaminidase cut the hemaglutinine-sialic acid contact allowing the bacterium infect more cells.
Syderophores: Bacterium proteins that allow iron caption for protein synthesis.
Transmission: Oral secretions and respiratory secretions, exudates lesions (are more infecting than respiratory secretions). There are normal carriers and can transmit disease only on endemic or epidemic ways. Also with food ingest (e.g. milk).
Pathology
There are two diphtheria types: respiratory and skin diphtheria.
Respiratory: Nasal anterior, oral, larynx. All of those can spread by blood and cause carditis, tubular necrosis and demielinization (which can express as facial muscles deficiency).
Nasal an Oral: Usually express with a white pseudo membrane in nasal septum and tonsils that goes and meets on the oral backside.
Larynx: Regularly is an oral extent that brings edema, nodes and “bull-neck”
Skin: Usually express like skin eruptions with exudates.
Is a gram + bacteria, capsulated, no spore former, usually as strains, facultative anaerobic, hemolytic. Perform β- hemolysis, and can be classified by his wall carbohydrate (Lancefield) or by his M protein.
Pathogenesis and virulence factors
Adhesion: Requires M protein, F protein, Capsule, Lipoteicoic Acid – Links Epithelium fibrinogen.
Internalization: Use M protein and F protein.
Anti-phagocyte Characteristics: M protein can bind to H factor that inactivate C3b, and bind fibrinogen that blocks C3b membrane union. MRP (M related proteins) binds to albumin, fibrinogen, IgA and IgG, plasminogen that inhibits phagocyte function. Otherwise, Capsule has intrinsic anti-phagocyte function. C5a peptidase can cut this chemocine.
Invasion: It’s up to M protein and Capsule.
Tissue Spread: DNA nuclease can eliminate DNA residues, hialuronidase allow tissue transition, streptoquinase allow the bacteria cut a clot and spread to all tissues, Cystein protease can eliminate cell residue.
Periphery Toxicity: Encompasses O streptolisine, S streptolisine and Sp-exotoxines. SpeA:STSS
Epidemiology
There are some nasal carriers, and transmission is: oral and nasal secretions, rheumatic fever occurs after pharingytis, acute glomerulonephritis occurs after skin or respiratory infection.
Rheumatic Fever: Has a latency period od 20 days, is recurrent and long time effects. Disease occurs when M protein mimics tropomyosin and myosin. Also, Group A carbohydrate mimics a valvular glycoprotein, Is not related with genus or race but economic status.
Jones’s Diagnostic Criteria: with 2 mayors or 1 mayor with 2 minor’s factors. Mayor’s: Migratory poliarthritis, carditis, marginal erythema, subcutaneous nodes and chorea. Minor’s: Fever, arthralgia, elevated PCR or GSS, and PR increase on EKG. Chorea: Molecular mimicry for losoganlioside and N-acetyl glucosamine.
Panda’s: Same last mechanism but different expression: obsessive compulsive disease, TIC’s and tourette syndrome.
Glomerulonephritis: Express like a nephritic syndrome because a molecular mimicry of M protein with kidney’s basement membrane and complex deposit. A latency period of 1 month.
An auto-immune disease is defined as an inflammatory response due auto-antigens. There is information about some infectious antigens can elicit auto-immune response. This is probably a regulatory fail, like negative selection in immune maturation. Hence, BC and TC have an elevated affinity for auto-antigens.
There are many mechanisms described which explain some auto-immune diseases:
Molecular mimicry: In this case, the infection allows the immune system to perform a response but some antigens are very similar to auto-antigens, so, the immune system reacts against body proteins. (i.e. rheumatic fever, Guillain Barre Syndrome, E.lyme arthritis)
Super antigenic response: There are proteins usually belong to gram + bacteria and virus that can link the MHC-II in his native way on the outside and can link non specifically TCR on his β chain in the variable region, with this union the BC and TC proliferate clonally. Hence, those superantigen proteins can stimulate auto reactive cells to proliferate and be deleterious. (i.e. B enteric toxin can stimulate TC proliferation against MBP (myelin basic protein) and elicits an experimental allergic encephalomyelitis).
Spectator Effect: Some immune cells don’t react against antigens but can proliferate because the cytokines release, in some cases the cells could be auto-reactive.
APC activation: Could happen that antigen presenting cells don’t recognize some kind of antigens on his immature phase, so, when they mature can recognize them and present them to TC that are very reactive against them because they don’t knew them.
Antigen release and transformation: Some apoptotic cells can express antigens on their membrane like ribonucleoprotein in erythematous lupus, this antigen elicit anti-DNA antibody production. Therefore, some proteins like anti-bodies, signaling proteins and others, are changed by biochemical mechanisms like acylation, citrulination, glycolization, and others. There is evidence that very proteins are changed in auto-immune diseases, like arthritis, multiple sclerosis, SEL.
Epitope Spread: When the TC reacts against some epitope of certain antigen, it could happen that this epitope change, so, the cell chooses another peptide region to link. In this way, TC could have more chances for develop a molecular mimicry response.
Immune complexes Deposit: The immunity complexes can be deposited in vessels, joints, kidneys and lungs. This complex can develop an inflammatory response on the deposit site. (i.e. group a streptococcus acute glomerulonephritis has been very studied)
Referencies:
¿La infección: inductor o reguladora de autoinmunidad? – Toro, Fabiola – 2004 – Anuario de enfermedades infecciosas – Universidad de Antioquia
Parvovirus is a nude virus type with DNAss(single strand) that can has both polarities, aproximately 50% (+) and 50% (-). The virus can resist a long range of Ph (3-9) and 60 minutes at 56ºC. Core is composed by VP1, VP2 and VP3, the structural proteins creating an icosaedric core with aproximately 12-32 capsomers. VP2 encompasses 80% virion mass. NS1 is functional protein necessary for replication. It can be inactivated by formalin.
Replication
The virus tropism is for replicating cells (going through S or G1 phase) because he is incapable of doing it. The virus doesn't count with the machinary for replication, so, needs host cell enzymes. The B-19 can stablish two types of infection permissive persistent and non permissive persistent. The first group of cells is composed by erythroblasts and erythroid progenitors (from bone marrow and fetal liver); the second group is composed by hepatic cells, endothelium, megacariocytes, BC, TC, mast-cells, Macrophages, epithelium and sinovium cells, fetal liver cells, fetal heart cells and placenta. The permissive kind allows the virus to destroy the cell and release virions. the non permissive kind go through apoptosis and stops viral spread.
Initially, the virus links this kind of cells via P antigen (globoside) and goes to the nucleus and is transcrypted and spliced, then RNAm is translocated to endoplasmic reticulum for protein synthesis. All of this come back to the nucleus, where VP1, VP2 and VP3 become the core and NS1 allow the DNA replication and core packing, this new virion can be (+) or (-) polarity. Last, if the cell is permissive there are cell lysis and virion release, if don't, the cell goes through apoptosis.
Pathology Spectrum
The pathology is up to the infected person. In pregnant womans, can be described in two ways: infectious erythema and hydrops fetalis. In inmunodeficient patients can appears as pure red cell aplasia and transient aplastic crisis. In inmunocompetent patients can appear like infectious erythema, arhtritis, SEL, sholein-henoch purpura, encephalitys.
Viral pathogenesis
In permissive cell there are lysis, in non permissive cells there are cytotoxicity because of NS1, in erythroblasts there are apoptosis because of NS1, ann lastly in all of them there are chronic inflamatory response.
Inmunopathogenesis
Anti-body production of IgG-VP1 that can have cross reaction against type II colagen and queratine.
Antibody production against viral antigens and deposit.
NS1 can elicit in endothelium, IL-6 release that stimulate BC to proliferate in a polyclonal way.
Laboratory
At the week of current infection, there are Ig-M, later, after the second week there are IgG that stay elevated very long time. About symptoms: at the week of curret infection there are fever, headache, malaise. In the 2-3º week there are RASH and anthralgias.
The Shell is conformed by protein c which creates dimers of protein c. Then, the dimers unites into oligomers and can create 90 icosaedral capsomers (t=3) or 120 icosaedral capsomers (t=4).
The protein c is like an upside down “T” in wich the horizontal bar mediates the dimer conformation and the vertical bar forms a spike protruding outside the virion. This spike has an epitope HBcAg.
Envelope proteins
The three proteins S,M and L are transcripted by the same region because an ORF in one area call E. Depending on which codon of the three do use the cell. The protein S are synthesized in ER (E. reticulum) as a transmembrane protein with two segments and with the loop segment in the lumen of the ER N- glycosilated, this brings the HBsAg epitope, which is very immunogenic and is usually used in vaccination. With protein M occurs similar but Protein L can folde in two ways: one with the loop (containing Pre-S1) outside of the virion or another with the same inside. This last fact is functionally unknown. During HBV nucleocapsid formation, the RNA pregenome is packaged into the particle’s lumen and first converted into single stranded and than into partially double-stranded DNA.
Pathogenesis
Hepatitis B virus (HBV) is a small DNA virus and belongs to a group of hepatotropic DNA viruses (hepadnaviruses)[1,2]. The virus consists of a nucleocapsid and an outer envelope composed mainly of three hepatitis B surface antigens (HBsAgs) that play a central role in the diagnosis of HBV infection. The nucleocapsid contains hepatitis B core antigen (HBcAg), a DNA polymerasereverse transcriptase, the viral genome as well as cellular proteins[1,2].
The genome consists of a partially double-stranded circular DNA molecule of about 3200 base pairs in length with known sequence as well as genetic organization. The pre-surface 1 [pre-S1]/pre-surface 2 [pre-S2]/and surface genes [S] code for the various HBsAgs. The protein encoded by the pre-core [pre-C]/core gene [C] undergoes post-translational modifi cation to yield hepatitis B e antigen (HBeAg), which is a seromarker for high viral replication[2]. The core gene codes for HBcAg, the major structural protein of the nucleocapsid. Finally, the X gene codes for the hepatitis B x antigen (HBxAg).
Seronegative patients for HBeAg
Some patients have infection due HBV but are seronegative because they had a previous infection with some mutant virion encoding a pre-C/C mutant that has a translation stop codon and the new virions don’t express the HBeAg but still replicating and are functionally active. These seronegative patients may be in very states of hepatitis: fulminant hepatitis, chronic hepatitis, self-limiting and asymptomatic hepatitis.
Core promoters variants
One mutation on core promoter enhancer II at two distinct points is associated with more aggressive disease. This variation can elicit chronic hepatitis or fulminant hepatitis.
Immune response
Response is basically by CTL that can eliminate HBV using cytopathic mechanism stead the noncytopathic elimination using INF α, γ. This response is polyclonal and specific. Hence, in chronic disease most probably the CTL are anergic, exhausted or there is an abnormal situation that mute them like disease or mutation.
Replication
Replication of the hepadnaviral genome can broadly be divided into three phases: (1) Infectious virions contain in their inner icosahedral core the genome as a partially double-stranded, circular but not covalently closed DNA of about 3.2 kb in length (relaxed circular, or RCDNA); (2) upon infection, the RC-DNA is converted, inside the host cell nucleus, into a plasmid-like covalently closed circular DNA (cccDNA); (3) from the cccDNA, several genomic and subgenomic RNAs are transcribed by cellular RNA polymerase ; of these, the pregenomic RNA (pgRNA) is selectively packaged into progeny capsids and is reverse transcribed by the co-packaged P protein into new RC-DNA genomes. Matured RCDNA containing-but not immature RNA containingnucleocapsids can be used for intracellular cccDNA amplification, or be enveloped and released from the cell as progeny virions. Below we discuss these genome conversions, with emphasis on the reverse transcription step, and particularly its unique initiation mechanism.
Persistent viral infections require that the viral genome be present in the infected cell in a stable form that is not lost during cell division, and which therefore can be used for the continuous production of progeny genomes. For hepadnaviruses, the genome persists, instead, as a nuclear, episomal covalently closed circle, i.e. the cccDNA.
Distinct features of the RC-DNA (Figure 2) are (1), only the (-)-DNA strand (with opposite polarity to the mRNAs) is complete whereas the (+)-strands comprise a cohort of less than full-length molecules; (2), the 5´ end of the (-)-DNA is covalently linked to P protein; (3) the 5´ end of the (+)-strand consists of an RNA oligonucleotide, derived from the pgRNA, which served as the primer for (+)-strand synthesis. For cccDNA formation, all these modifi cations need to be removed, and both strands need to be covalently ligated.
The protein p is not related with RC-DNA conversion. In transcription a few virions can have others transcripts different of PgRNA but they are unfunctional, the correct transcription is up to post-transcriptional regulatory element (PRE).
The Pg-RNA is mainly the mRNA for p protein and core proteins and second for new synthesis of RC-DNA. RNA polymerase can fail the transcription in an uncounted amount. The Pg-RNA and p protein are encapsulated thanks to the epsilon union that allows the dimers of c protein to initiate the packing. This epsilon region (5’ Pg-RNA) contact ensures that the p protein starts the reverse transcription of the new - RC-DNA using the Pg-RNA. The capsids are essential for RC-DNA synthesis.
Oncogenesis
HCC (hepatocelular carcinoma) is more frecuent in men than in women. Chronic infection by HBV is a risk factor, others factors include: HCV chronic infection, aflatoxin b exposure, alcohol, obesity and diabetes.
HBV is found to be integrated in the host genoma frecuently, but there is not consistent data that ensures an oncogen activation.
HBxAg is a small protein that has been related with oncogenesis. Apparently, interferes with cell transcription, with p53, with DNA reparation, with normal signaling cascades of cell growing.
Pre-S2 activator proteins encompasses a group of proteins that can elicit HCC. Ths surface protein L has a Pre-S2 domain that can initiate a signaling cascade via PKC.
“…Immune pathogenesis of HCC A major factor in the process of HBV-associated HCC development is the immune system[104,106,107]. The relevance of a chronic, virus-specific immune response for development of HBV-associated carcinoma was shown in an elegant experiment from F. Chisari`s laboratory[108]. Transgenic mice that produce non-cytopathic amounts of HBsAg were used. In these mice, immunologic tolerance against the transgene product can be observed. In accordance with this, no evidence of the liver disease was observed. These mice were subjected to thymectomy and lethally irradiated. One group was reconstituted with the bone marrow and spleen cells derived from non-transgenic littermates that were vaccinated with a recombinant HBsAg encoding vaccinia virus resulting in HBsAgspecific cytotoxic T lymphocytes (CTLs) and antibodies. The other group was reconstituted with the bone marrow and spleen cells derived from transgenic donors that were immunologically tolerant. In this animal model, the development of hepatitis and later of chronic hepatitis and finally HCC development could be exclusively observed in the mice that were reconstituted with the bone marrow and spleen cells derived from the vaccinated non-transgenic animals, but not in the control groups. Based on this, it was concluded that the immune system-mediated chronic inflammation of the liver, continuous cell death and subsequent cell proliferation might increase the frequency of genetic alterations and the risk of cáncer…”
In other words, the same T-cell response can have complete different effects: if the T cell response is strong enough, HBV can be eliminated from the liver, if not, a pro-carcinogenic effect can be induced by permanently triggering necroinflammatory disease without resulting in a final eradication of HBV from the liver.
References: The world journal of gastroenterology http://www.wjgnet.com
Human tumors have been attributed to both human herpesvirus 8 (Kaposi’s sarcoma, primary effusion lymphoma, and Castleman’s disease) and to EBV (Burkitt’s lymphoma, nasopharyngeal Carcinoma, and Hodgkin’s and non-Hodgkin’s lymphomas Although herpesviruses are ubiquitous in nature, humans serve as the only natural host for EBV. It is now known that EBV infects _90% of the world’s adult population. Upon infection, the individual remains a lifelong carrier of the virus (2). EBV is transmitted by salivary contact. During acute infection, EBV primarily infects and replicates in the stratified squamous epithelium of the oropharynx (3, 4). This is followed by a latent infection of the B Lymphocytes. Virus can continue to be shed from the oropharynx into the saliva for years. Of interest, once the virus has colonized the B-lymphoid compartment, reactivation from latency can occur at any mucosal site where B cells reside (e.g., the cervix).
Morphology
EBV is a herpesvirus with a 184-kbp long, double-stranded DNA genome that encodes _85 genes (12). The viral genome consists of a series of 0.5-kb terminal direct repeats at either end and internal repeat sequences that serve to divide the genome into short and long unique sequence domains that have most of the coding capacity (13). EBV, as with other herpesviruses, has a toroid-shaped protein core wrapped with double-stranded DNA, a nucleocapsid with 162 capsomeres, a protein tegument between the nucleocapsid and envelope, and an outer envelope with external glycoprotein spikes.
When EBV infects a cell, the DNA becomes a circular episome with a characteristic number of terminal repeats, depending on the number of terminal repeats in the parental genome, with variation introduced during viral replication. If the infection is permissive for latent infection but not replication, future generations will have EBV episomes with the same number of terminal repeats.
Two subtypes of EBV are known to infect humans: EBV-1 and EBV-2. EBV-1 and EBV-2 differ in the organization of the genes that code for the EBV nuclear antigen (EBNA-2, EBNA- 3a, EBNA-3b, and EBNA-3c; Ref. 16). EBV-2 is less efficient in produce a tumor cell.
In normal individuals, the result is clinically apparent or milder forms of infectious mononucleosis.
Viral Products
EBNA-1: is a nucleoantigen protein that binds to DNA at multiple sites and elicits replication via host enzymes.
EBNA-2: is a nucleoentigen protein that work as transcription factor and can promote the transcription of proto-oncogenes (c-myc), cell markers (CD 23) via C promoter link.
EBNA-LP: is a protein that interactuate with EBNA-2 inducing b-cell in G1 phase by inhibiting P-53 and Rb-p.
EBNA 3a, 3b, 3c: Are transcription regulators. 3A and 3C are essential for immortalization. 3C may overcome Rb-p.
LMP-1: is a surface protein that mimics the CD-40 that links the usual ligand and trigger a signaling pathway involve in oncogenesis. Via Nf-KB, ATF1, AP-1, jun-nh2 terminal. Therefore, inhibits apoptosis by elevating levels of bcl-2.
EBER’s 1 y 2: immature DNA that can contribute to immortalization but nonessential.
The minimum requirement for membrane fusion to occur with epithelial cells is the coexpression of EBV envelope glycoproteins gH, gL, and gB. EBV additionally requires the gp42 protein for entry into B cells (11, 27, 28). EBV gp42 binds major histocompatibility complex class II (MHC-II) proteins expressed on B cells to trigger viral-cell membrane fusion.
Homologies:
BCRF1 and Il-10: similar in 86%, so EBV can inhibit inflammatory response and stimulate BC growth.
Latency types
I: EBNA1, EBER 1 y 2 – Linfoma de Burkitt
IIa: EBER1 y 2, EBNA1, LMP-1 Y LPM-2 – CA nasofaríngeo, linfoma hodgkin y no hodgkin.
III: 8 Ag y 2 RNA’s – Inmunocomprometidos, líneas celulares linfoblastoides, desordenes proliferativos pos-transplante.
Oncogenesis
To maintain viral DNA in the cell, EBV establishes latent infection in B lymphocytes. The EBV genome is maintained in these cells, either as a multicopy circular episome in the host cell or by integrating the viral DNA into the host genome. The virus thus ensures transmission to cell progeny when B lymphocytes replicate. EBV latent genes induce an activated phenotype in the infected B cells. Although these cells are not transformed, if they proceed unchecked or acquire oncogenic mutations, they can become neoplastic. In normal individuals, cytotoxic T-cell responses against latent viral proteins prevent the expansion these activated B cells. Through normal differentiation of these cells, EBV eventually enters the resting B-cell memory compartment.
Burkitt’s Lynphoma: is malignant proliferation because of translocation of chromosome 8 with chromosome 14,2 or 22. The mechanism is the adjunction of c-myc (chromosome 8) with another normal protein like a heavy chain IG.Is endemic when EBV is present.
Is not clear if EBV elicits a chromosome translocation. Indeed, in the endemic pattern involves less the bone marrow stead no-endemic pattern.
Hodgkin’s Disease: Is defined by proliferation of reed-sternberg cells wich has been postuladed to be part of BC lineage.
No hodgkin’s disease: It has been compromised with two types of neoplasias: nasal T/ natural killer non hodgkin’s lymphoma and angioinmunoblastic linphadenopathy.
Nasopharyngeal carcinoma: is related almost in every case for undifferentiated carcinoma, and can be caused by both types. Apparently, his entry into the cells is via endocytosis with Ig-A or by a receptor, most probably CD 21.
Gastric carcinoma: Apparently related with linphoepitelioma-like carcinoma because the EBV in nasopharyngeal region can spread to the stomach.It's also been involved in leiomyosarcoma and breast cancer.
Dx: The presence of antibody of the IgM type to the viral capsid antigen is indicative of current infection. Antibody of the IgG type to the viral capsid antigen is a marker of past infection and indicates immunity.
References - Epstein Barr, Virus and Cancer. Matthew P. Thompson and Razelle Kurzrock. University of Texas. 2004.link - Jawetz - Microbliology - 24 edition
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