C24 Viral infection and immunity

樊晓晖 教授

Section I Mode of viral infection

Horizontal Transmission

vertical infection

第 24章 病毒的感染与免疫

Direct person-to-person spread.

Relies on PERSISTENCE of the agent to transfer infection from parents to offspring.

Transmission and portal of entry

• Vertical transmissionVertical transmission

• Horizontal transmissionHorizontal transmission

Several forms of vertical transmission can be distinguished:

• 1.Neonatal infection at birth, e.g. gonorrhorea, AIDS.

• 2.Infection in utero e.g. syphilis, CMV, Rubella (CRS), AIDS.

• 3. Germ line infection - via ovum or sperm.

Section II Types of viral infection

第 24章 病毒的感染与免疫

1 、

Inapparent infection ( Subclinical infection) .

Apparent infection

2 、Acute infection

Chronic infection

3 、 Persistent Infection

chronic latent Slow virus infections

Persistent Infection•① Chronic Infection ： Virus can be

continuously detected ; mild or no clinical symptoms may be evident.

•② Latent infection ： The Virus persists in an occult, or cryptic, from most of the time. There will be intermittent flare-ups of clinical disease , Infectious virus can be recovered during flare-ups . Latent virus infections typically persist for the entire life of the host

•③ Slow virus infection ： A prolonged incubation period, lasting months or years, daring which virus continues to multiply. Clinical symptoms are usually not evident during the long incubation period .

第 24章 病毒的感染与免疫

带状疱疹 ( 水痘病毒感染后潜伏在脊髓后跟 N 节 )

Mechanism of Persistent Infection

• Immunity is weak ；• Viral antigenicity is weak ；• Viruses is in protective position ；• Viral variation ；• Viral genes integration.

•Processes and fates of infections

第 24章 病毒的感染与免疫

Infection processes ：1. local

2. systemic

Infection fates ：

1. die

2. Subclinical infection

3. Abortive infection

4. Recover

•Animal model

Section III Pathogenicity of viruses

第 24章 病毒的感染与免疫

I. Effects of viral infection on cellsI. Effects of viral infection on cells

• According to the interaction between host cells and viruses

cytocidal effect include Steady state infection Apopotosis Transformation Integrated viral infection Formation of inclusion body

Cytocidal infectionCytocidal infection

•Severe ， cells lyse and die

•Occur in non-enveloped

virus

•Cause Cytopathological effects(CPE) Cells roundingDegeneration,AggregationLoss of attachments to substrate

上皮细胞 epithelial cells – 腺病毒 adenovirus

uninfected early infection late infectionslides from CDC

上皮细胞上皮细胞 epithelial cells – epithelial cells – 呼吸道合胞病毒呼吸道合胞病毒 respiratory syncytial virusrespiratory syncytial virus

uninfected respiratory syncytial virusslides from CDC

纤维母细胞纤维母细胞 fibroblastic cells – fibroblastic cells – 单纯疱疹病毒单纯疱疹病毒 herpes simplex virusherpes simplex virus

uninfected early infection late infectionslides from CDC

纤维母细胞纤维母细胞 fibroblastic cells – 脊髓灰质炎病毒 poliovirus

uninfected early infection late infectionslides from CDC

•Blocking synthesis of cellular protein and nucleic acid

•Toxicity of viral protein •Affect cellular lysosome•Alter the cellular organ 。

Viral early protein

Some capsid

destroy

injury

Pathogenicity:Pathogenicity:

稳定状态感染Steady state infection稳定状态感染Steady state infection•Enveloped viruses, •Without lyses of cells•Release by budding

•Change of cell membrane

•Formation of auto antigen and fusing of cells

Fig A multinucleate giant cell

细胞凋亡 apoptosis

HIV

Cell transformation,

SV40

Integration of viral genesIntegration of viral genes•DNA viruses and retro-viruses•The viral genetic information

may become integrated as DNA in the cellular genome or may persist as episomal DNA in these surviving cells.

•Oncogenic transformation occur•New antigen appears.

Interaction between viruses and hostsInteraction between viruses and hosts

• Types of infection.

– HBV: steady and integration infection

– Herpesviruses: Cytocidal,steady and integration infections.

– Most viruses, only one type infection

二 、 Effects of virus infection on immune system二 、 Effects of virus infection on immune system

• Inhibit or destroy immune system

• Pathological effects caused by

humorol immunity

• Pathological effects caused by

cellular immunity

Inhibit or destroy immune systemInhibit or destroy immune system•HIV

•Measle virus

Pathological effects caused by humorol immunityPathological effects caused by humorol immunity

• Viruses infect cells, new Ag present on cell membrane →type Ⅱ hypersensitivity damage cells

• Viral Ag combines with Ab, precipitate on basic membrane of blood vessel→ type III 型 hypersensitivity damage cells.

Pathological effects caused by cellular immunityPathological effects caused by cellular immunity•Viruses infect cells, new Ag

present on cell membrane → recognized by specific CTL) type IV hypersensitivity kills cells

Innate immunity（ nonspecific ）

Adaptive immunity（ specific ）

IFN

NK cellsHumorol immunity

Cellular immunity

Section 4 Anti-virus immunitySection 4 Anti-virus immunity

IFNIFN• Interferons are proteins produced by

cells infected with viruses, or exposed to certain other agents, which protect other cells against virus infection or decrease drastically the virus yield from such cells. Interferon itself is not directly the anti-viral agent, but it is the inducer of one or many anti-viral mechanisms

Interferon inducing agents

• (1) Viruses. • (2) dsRNA is a potent inducer, both viral

intermediates, and synthetic polyI-C.  • (4) Certain Bacterial infections, and the

production of endotoxin.  • (5) Metabolic activators/inhibitors.

Mitogens for gamma induction, also a variety of tumor promoters induce IFNs. , in particular PTA-phorbol tetradecanoate acetate, butyrate, dexamethasone

Kinds and sources IFNsKinds and sources IFNs

Kinds Principal cell source

INF-α Epithelium

and leukocytes type I IFN

IFN-β Fibroblasts IFN-γ T lymphocytes typeⅡ IFN

Mechanism of actionMechanism of action• Release from an initial infected cell occurs• IFN binds to a specific cell surface receptor on an

other cell• IFN induces the “antiviral state” : synthesis of

protein kinase, 2’5’ oligoadenylate synthetase, and ribonuclease L

• Viral infection of the cell activates these enzymes• Inhibition of viral and cellular protein synthesis

occurs

Application of IFNsApplication of IFNs•Anti viral infection•Anti tumor treatment•Immuoregulation 。

Diseases currently treated with IFN-alpha and IFN-beta

• hepatitis C • hepatitis B• papilloma warts and early trials with cervical

carcinoma• Kaposi sarcoma of AIDS, • colon tumors• kidney tumors ( usually in combination with other

drugs). • Basal cell carcinoma• Breast cancer combined with tamoxifan.

Nature killer/ NK cell

•NK cells are Activated by IFN-alpha/beta

•NK cells are Activated by IFN-alpha and IL-2 and

Activate macrophage

•NK cells target and kill virus infected cells

NK cell

Macrophages

• Macrophages filter ciral particles from blood

• Macrophages inactivate opsonized virus particles

• Macrophages present viral antigen to CD4 T cells

Complement

• Enhancing neutralization of Antibody

• Enhancing phagocytosis of virus particles

• Lysis

二 Specific anti-viral immunity二 Specific anti-viral immunity

•humorol•cellular

Overview of Specific immunity

• specific recognition and selective elimination of foreign molecules.

• Involves specificity, diversity, memory, and self/nonself recognition.

Humorol immunityHumorol immunity• Abs against viruses

– NeutrolizationAb:IgG 、 IgM 、 IgA – nonneutrolizing: otherantibody

• Extracellular viral infections　　　　　　　　　　　

AntibodyIgG IgM IgA

Function Memory

Blood and

tissue

Primary response

Clear viruses in blood

Mucus immunit

y

C: classic pathway

+++ - -

C : C3 pathway - - +

placenta +++ - -

ADCC ++ - -

Antibody Antibody neutralizes extracellular virue:

it blocks viral attachment proteins

it destablilizes viral structure

Antibody opsonizes virus for phagocytosis

Antibody promotes killing of target cell by the complement cascade and antibody-dependent cellular cytotoxicity

Antibody resolves lytic viral infections

Antibody blocks viremic spread to target tissue

IgM is an indicator of recent or current infection

IgG is more effective than LgM

Secretory IgA is important for protecting mucosal surfaces

Neutralization antibodyNeutralization antibody

•Neutralization ： Neutralization antibody binds virus to terminate the viral infectivity

Mechanism of neutralization Ab:Mechanism of neutralization Ab:

• Block viruses to attach and penetrate

• Virus combine with Ab to immune complex, facilitate the phygocytosis of macrophage

• Ab combines with enveloped virus, activate complement to lyse virus

Cellular immunity Cellular immunity •Intracellular viral infection•CTL•DTH

Maintaining duration of anti-viral immunityMaintaining duration of anti-viral immunity

•Varied by different viruses, •Factors

–Viral antigenecity is single or steady

–Viramia–Variation of virus surface Ags.

Summary

• The ability of viruses to cause disease can be viewed on two distinct levels: (1) the changes that occur within individual cells and (2) the process that takes place in the infected patient.

• The fundamental process of viral infection is the viral replication cycle in a host cell. The cellular response to that infection may range from cell death or cancer to no apparent effect.

• The host response to an invading virus will depend upon the types of the infectious agent and where it is encountered.

• Virus infections may be clinical, sub -clinical, acute, chronic, latent, and delayed.

• Interferons (IFNs) are host - coded proteins of the large cytokine family that inhibit viral replication and can modulate humoral and cellular immunity.

• Host defenses against viruses fall into two major categories: (1) nonspecific, of which the most important are interferons; and (2) specific, including both humoral and cell-mediated immunity.

复习思考题复习思考题• 何为垂直传播？何为水平传播？• 病毒感染的类型有哪些？• 病毒对宿主细胞有哪些直接作用？• 名词解释： 水平传播（ horizontal

transmission ）潜伏感染（ latent infection ）整合（ integration ）包涵体（ inclusion body ）

• 试简述干扰素的概念、种类、作用及其抗病毒的主要机制