Infections Caused by Other Intracellular Bacteria

Slide 1 · Infections Caused by Other Intracellular Bacteria

Rickettsial, oriential, ehrlichial and anaplasmal infections

Mechanisms • Vascular pathology • Clinical and morphologic recognition

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish the four genera by syndrome, vector, and preferred infected cell.

Explain how rickettsial endothelial infection produces vascular injury and systemic illness.

Recognize typhus, scrub typhus, and spotted-fever morphology.

Relate ehrlichiosis and anaplasmosis to leukocyte morulae and clinical presentations.

Slide 3 · A defined group of obligate intracellular bacteria

Rickettsia

Epidemic typhus and spotted fevers

Orientia

Scrub typhus

Ehrlichia

Ehrlichiosis

Anaplasma

Anaplasmosis

The shared intracellular lifestyle does not imply identical target cells or pathology.

Slide 4 · Intracellular growth requires host cells

Intracellular niche

Replication only within a host cell

Nutrient acquisition

Host amino acids and glucose-6-phosphate

Bacterial synthesis

Resources support protein and ATP synthesis

The host cell is both a replication compartment and a nutrient source.

Slide 5 · Gram-negative architecture; Poor Gram-stain visibility

Bacterial structure

Rod-shaped bacterial morphology

Structural features of gram-negative bacteria

Routine staining caveat

These organisms stain poorly with Gram stain.

Failure to see organisms on a Gram stain does not exclude infection.

Slide 6 · Vector links separate the major syndromes

Syndrome

Major organism

Transmission

Epidemic typhus

R. prowazekii

Body/head lice

Scrub typhus

O. tsutsugamushi

Chiggers (mites)

Rocky Mountain spotted fever

R. rickettsii

Dog ticks

Ehrlichiosis / anaplasmosis

E. chaffeensis / A. phagocytophilum

Lone star / deer ticks

Slide 7 · The infected cell predicts the lesion

Endothelial infection

Typhus and spotted-fever rickettsiae infect vascular endothelium.

Vascular permeability, thrombosis, and organ dysfunction predominate.

Leukocyte infection

E. Chaffeensis predominantly infects monocytes.

A. Phagocytophilum predominantly infects neutrophils.

Slide 8 · A practical recognition framework

Exposure

Louse, mite, or particular tick

Distribution

Characteristic rash or eschar

Compartment

Vessels versus circulating leukocytes

Mechanism + vector + morphology provide a stronger classification than fever alone.

Slide 9 · Four clinical syndromes, four distinguishing clues

Disease

Characteristic clue

Primary pathology clue

Epidemic typhus

Louse exposure; rash usually spares palms/soles

Endothelial swelling; mononuclear cuffs

Scrub typhus

Mite exposure; possible eschar

Lymphadenopathy; less vascular necrosis

RMSF

Tick exposure; palms/soles may be involved

Small-vessel necrosis and fibrin

Ehrlichiosis / anaplasmosis

Tick exposure; systemic febrile illness

Morulae within leukocytes

Slide 10 · Rickettsial severity begins in endothelial cells

Tissue tropism

Endothelium; Notably lungs and brain

Cellular injury

Endothelial dysfunction

Vascular consequences

Edema, thrombi, and hemorrhage

Clinical consequences

Shock and organ injury

The endothelial cell is the central pathophysiologic target.

Slide 11 · Cell entry starts by endocytosis

Contact

Bacteria encounter susceptible endothelial cells

Endocytosis

Host cell internalizes organisms

Endosomal compartment

Bacteria enter a membrane-bound vesicle

Cell entry is distinct from the next step: Endosomal escape.

Slide 12 · Hemolysins enable escape from the endosome

Endosome

Internalized bacteria remain enclosed

Hemolysin action

Phagosomal membranes are disrupted

Cytoplasm

Bacteria reach a permissive replication site

Escape into cytoplasm is a key rickettsial survival mechanism.

Slide 13 · Intracytoplasmic proliferation changes endothelial integrity

Cytoplasmic proliferation

Organisms multiply in the cell

Infected cell response

Cell dysfunction or injury

Tissue effect

Vessel barrier becomes pathologic

A microscopic intracellular event can cause distributed vascular disease.

Slide 14 · Two distinct exits from infected cells

Intracellular stage

Cytoplasmic growth in infected endothelium

Typhus group

Cell lysis

Spotted fever group

Actin-based cell-to-cell spread

The source explicitly distinguishes these two mechanisms of propagation.

Slide 15 · Typhus-group propagation involves cellular lysis

Rickettsial growth

Accumulation in cytoplasm

Host-cell lysis

Infected endothelial cell is destroyed

Widespread infection

Further endothelial dysfunction

Cell lysis explains one mechanism for vascular barrier injury.

Slide 16 · Spotted-fever rickettsiae use actin-based motility

Cytoplasmic bacteria

Actin-based motility

Cell-to-cell spread

Propagation to adjacent cells

Vascular lesion

Continued endothelial involvement

The spotted-fever group can spread without relying solely on host-cell lysis.

Slide 17 · Endothelial swelling narrows the vascular lumen

Small-vessel cross-section · original schematic

Narrowed lumen

Capillaries, arterioles, and venules are affected.

Swollen endothelium reduces the available vessel lumen.

Impaired microvascular passage contributes to tissue injury.

Slide 18 · Increased permeability produces interstitial edema

Endothelial dysfunction

Injured vascular barrier

Fluid movement

Edema develops in peripheral tissues

Pulmonary involvement

Pulmonary edema may impair breathing

The same small-vessel lesion has different effects in different organs.

Slide 19 · Vascular thrombosis intensifies ischemic injury

Small-vessel cross-section · original schematic

Thrombus

Intraluminal thrombus

Vascular lumens can become thrombosed.

Thrombi reduce local blood flow.

Severe focal ischemia may cause tissue necrosis.

Slide 20 · Severe endothelial injury may produce DIC

Disseminated endothelial damage

Systemic vascular dysfunction

Coagulation disturbance

Disseminated intravascular coagulation

Clinical threat

Shock and multiorgan involvement

DIC is a potential consequence, not a universal presentation.

Slide 21 · Renal injury and shock are vascular consequences

Renal effects

Widespread endothelial dysfunction can compromise renal function.

Renal failure is among the severe complications.

Systemic hemodynamics

Vascular dysfunction may contribute to shock.

Concomitant pulmonary edema and DIC can worsen severity.

Slide 22 · CNS manifestations reflect brain vascular tropism

Brain endothelial infection

High-risk vascular site

CNS vascular dysfunction

Local hemorrhage or ischemic consequences

Clinical manifestation

Neurologic impairment, including coma

CNS disease is linked to vascular pathogenesis, not just systemic fever.

Slide 23 · Endothelial lesions connect skin and organ manifestations

Organ / tissue

Mechanistic lesion

Pathologic / clinical result

Skin

Vascular leakage and thrombosis

Petechiae, necrotic lesions

Brain

Vascular injury; focal inflammation

Microglial nodules or microinfarcts

Lungs

Vascular dysfunction

Pulmonary edema, respiratory compromise

Kidneys

Microvascular injury

Renal dysfunction / failure

Slide 24 · Innate defense includes NK-cell interferon-γ

Rickettsial infection

Innate immune recognition

Natural killer cells

Production of interferon-γ

Macrophage activation

Bactericidal nitric oxide derivatives

NK-cell signaling promotes an antimicrobial macrophage response.

Slide 25 · Macrophage nitric oxide contributes to bacterial killing

Signal

NK cells produce IFN-γ during the innate response.

IFN-γ stimulates macrophages.

Effector

Macrophages generate bactericidal nitric oxide derivatives.

This limits survival of intracellular organisms.

Slide 26 · Cytotoxic T lymphocytes act later

Persistent infected host cells

Intracellular bacteria remain present

Cytotoxic T lymphocytes

Lysis of infected host cells

Result

Reduced bacterial proliferation

Cell-mediated immunity is central to defense against intracellular pathogens.

Slide 27 · The host response develops in phases

Early

NK cells and IFN-γ

Effector

Activated macrophages; Nitric oxide

Later

CTL-mediated lysis of infected cells

A conceptual sequence from the textbook—not a quantitative timeline.

Slide 28 · Vascular injury is the unifying morphologic principle

Barrier injury

Edema and hemorrhage

Luminal injury

Thrombosis and ischemia

Inflammatory response

Perivascular mononuclear infiltrates

Different organisms vary in severity and pattern of these features.

Slide 29 · Epidemic typhus is caused by R. Prowazekii

Cause and transmission

Rickettsia prowazekii

Body and head lice mediate transmission.

Exposure setting

Crowding and inadequate hygiene

War and poverty facilitate outbreaks.

Slide 30 · The epidemiology reflects close-contact settings

Crowding / poor hygiene

Close human proximity

Body or head lice

Transmission between people

R. Prowazekii infection

Epidemic typhus

The social environment modifies vector exposure.

Slide 31 · Epidemic typhus rash changes with time

Early skin findings

Macular rash

Progression

Maculopapular and petechial changes

Distribution

Extensive rash with typical sparing areas

The evolution of rash reflects ongoing vascular injury.

Slide 32 · Typhus typically spares face, palms, and soles

Usually involved

Typically spared

Interpretation

Most of the body

Face

Distribution supports epidemic typhus

Trunk and limbs

Palms and soles

Compare with RMSF

Skin microvessels

—

Rash is a vascular manifestation

Slide 33 · Mild typhus may show little gross pathology

Mild cases may have a skin rash as the main visible finding.

Small hemorrhages result from vascular lesions.

Gross abnormalities need not reflect the full microscopic vascular disease.

Slide 34 · Severe typhus can cause peripheral gangrene

Ischemic trigger

Small-vessel thrombosis

Sites described

Fingertips, nose and ear lobules

Other sites

Scrotum, penis, and vulva

Cutaneous necrosis occurs in severe disease, not in every patient.

Slide 35 · Internal hemorrhage reflects systemic vasculopathy

Sites reported in severe typhus

Observed lesion

Brain and heart muscle

Irregular ecchymotic hemorrhages

Testes and serosal membranes

Irregular ecchymotic hemorrhages

Lungs and kidneys

Irregular ecchymotic hemorrhages

Slide 36 · Typhus microangiopathy involves small vessels

Small-vessel cross-section · original schematic

Narrowed lumen

Capillaries, arterioles, and venules are affected.

Endothelial swelling may narrow vascular lumens.

Hemorrhage and focal inflammation occur across organs.

Slide 37 · Mononuclear perivascular cuffs are characteristic

Small-vessel cross-section · original schematic

Mononuclear cuff

Mononuclear inflammatory cells encircle affected small vessels.

The infiltrate surrounds an abnormal endothelial-lined lumen.

This is a histologic pattern rather than an organism-specific stain.

Slide 38 · Vascular thromboses in typhus are variable

Small-vessel cross-section · original schematic

Thrombus

Intraluminal thrombus

Vessel lumens may contain thrombi.

Only a minority develop thrombosis-associated ischemic necrosis.

Vessel-wall necrosis is unusual compared with RMSF.

Slide 39 · Typhus nodules are focal inflammatory lesions of the brain

Microglia

Focal microglial proliferation

T lymphocytes

Part of the mixed cellular infiltrate

Macrophages

Coexist with the T-cell infiltrate

The combination forms the characteristic typhus nodule.

Slide 40 · Typhus nodule: Constituent cells

Original conceptual schematic · not a microscopy image

Microglia + T cells + macrophages

Focal microglial proliferation forms the central feature.

Mixed T lymphocytes and macrophages accompany the microglia.

The drawing is a compartmental schematic, not a brain photomicrograph.

Slide 41 · Typhus: Correlate skin, vessel, and brain

Level

Finding

Why it matters

Clinical

Evolving widespread rash

Vascular injury at the skin

Microscopic vessel

Swelling and mononuclear cuffs

Small-vessel pathology

Severe disease

Thrombosis and ischemic necrosis

Threatened tissue perfusion

Brain

Typhus nodules

Characteristic neuroinflammatory lesion

Slide 42 · Scrub typhus is an Orientia infection

Organism and vector

Orientia tsutsugamushi

Transmitted by chiggers (mites).

Source-described geography

Rural Asia and Australia

Reported emergence in South Korea, Chile, and parts of China

Slide 43 · A chigger bite can produce an eschar

Chigger exposure

Cutaneous inoculation

Bite-site lesion

Characteristic eschar may be present

Local response

Associated lymphadenopathy

The eschar is helpful when present, but not obligatory.

Slide 44 · Scrub typhus often presents as a systemic febrile illness

Usual symptoms are fever, headache, and myalgia.

Cough may accompany systemic symptoms.

A characteristic eschar and regional lymphadenopathy are possible clues.

The rash may be transient or absent.

Slide 45 · Scrub typhus differs morphologically from severe typhus

Scrub typhus

Vascular necrosis or thrombosis is rare.

Inflammatory lymphadenopathy may be prominent.

Rash is often transient or absent.

Epidemic typhus

Small-vessel changes and hemorrhage are prominent.

Thrombosis may produce ischemic necrosis.

Widespread evolving rash is described.

Slide 46 · RMSF is a tick-borne spotted fever

Agent and transmission

Rickettsia rickettsii

Dog ticks transmit infection to humans.

Distribution described

Southeastern and south-central United States are emphasized.

Also occurs elsewhere in the Americas.

Slide 47 · Early RMSF may be clinically nonspecific

Onset

Fever and myalgias

Early systemic symptoms

Gastrointestinal distress

Later pattern

Widespread macular, then petechial rash

Do not expect the characteristic rash at the first symptomatic moment.

Slide 48 · Palms and soles help distinguish RMSF rash

Rocky Mountain spotted fever

Macular rash progresses to petechiae.

Palms and soles can be involved.

Epidemic typhus

Macular eruption also becomes petechial.

Palms and soles are typically spared.

Slide 49 · Eschar is uncommon in RMSF

The infection is transmitted by tick bite.

An eschar at the inoculation site is uncommon with RMSF.

An eschar is more characteristic of scrub typhus when present.

The rash distribution and vascular pathology are more useful comparative clues.

Slide 50 · RMSF shows more destructive vessel-wall lesions

Small-vessel cross-section · original schematic

Thrombus

Necrotizing injury

Small vessels may undergo acute necrosis.

Fibrin can extravasate from injured vessels.

Thrombosis may involve arterioles and other small vessels.

Slide 51 · RMSF vasculitis explains the hemorrhagic rash

Vascular wall injury

Necrosis and fibrin leakage

Tissue consequences

Small-vessel hemorrhage

Cutaneous pattern

Petechial, hemorrhagic eruption

The rash is an outward manifestation of systemic vascular injury.

Slide 52 · Severe RMSF may produce distal skin necrosis

Digits

Fingers and toes

Prominent sites

Elbows and ears

Other described site

Scrotum

These foci reflect severe vascular compromise.

Slide 53 · RMSF affects multiple organ systems

Tissue

Source-described pathology / consequence

Brain

Perivascular inflammation; microinfarcts

Skeletal muscle

Perivascular inflammatory response

Lungs and kidneys

Perivascular inflammatory response

Testes and heart muscle

Perivascular inflammatory response

Slide 54 · Brain vasculopathy can produce microinfarcts

Brain vascular lesions

May involve larger vessels

Impaired perfusion

Focal tissue ischemia

Pathology

Microinfarcts

Brain lesions in RMSF are not limited to perivascular inflammatory cuffs.

Slide 55 · Severe pulmonary edema is a major lethal pathway

Endothelial dysfunction in pulmonary vessels

Microvascular barrier failure

Noncardiogenic pulmonary edema

Acute respiratory distress syndrome

Severe disease

Major cause of death described in RMSF

The source identifies pulmonary failure as a principal fatal complication.

Slide 56 · Typhus and RMSF: Pathologic discriminators

Finding

Epidemic typhus

RMSF

Endothelial swelling

Prominent

Possible in vascular disease

Vessel-wall necrosis

Unusual

May occur in affected vessels

Vascular thrombosis

Sometimes

Occasionally

Brain lesion

Typhus nodules

Vascular lesions with microinfarcts

Skin distribution

Palms/soles spared

Palms/soles may be involved

Slide 57 · Ehrlichiosis and anaplasmosis target leukocytes

Ehrlichiosis

Main organism: Ehrlichia chaffeensis

Predominant infected leukocyte: Monocyte

Anaplasmosis

Organism: Anaplasma phagocytophilum

Predominant infected leukocyte: Neutrophil

Slide 58 · Two tick associations, two cell targets

Feature

Ehrlichiosis

Anaplasmosis

Vector

Lone star tick

Deer tick

Organism

E. chaffeensis

A. phagocytophilum

Cell tropism

Monocyte

Neutrophil

Characteristic inclusion

Morulae

Morulae

Slide 59 · Morulae are bacterial inclusions in leukocytes

Original conceptual schematic · not a microscopy image

Morula

Neutrophil (anaplasmosis model)

Morulae are cytoplasmic clusters composed of masses of bacteria.

Their aggregates may have a mulberry-like appearance.

They may be seen in leukocytes in ehrlichiosis and anaplasmosis.

Slide 60 · Ehrlichiosis and anaplasmosis often begin abruptly

An abrupt onset of fever is typical.

Headache and malaise commonly accompany the fever.

Both diseases may have similar presenting symptoms.

The infected leukocyte type provides an etiologic distinction.

Slide 61 · Rash is variable in ehrlichial and anaplasmal disease

Ehrlichiosis

Rash occurs in approximately 40% of E. Chaffeensis infections.

Macular, maculopapular, or petechial morphology may occur.

Both infections

Rash is nonspecific when present.

Absence of rash does not negate the source-described febrile syndrome.

Slide 62 · Severe ehrlichial or anaplasmal illness can escalate

Abrupt febrile illness

Headache and malaise

Severe systemic disease

Respiratory insufficiency

Organ dysfunction

Renal failure and shock

These are possible complications, not automatic consequences.

Slide 63 · Leukocyte morulae do not imply vascular-wall necrosis

Ehrlichia / Anaplasma

Characteristic inclusion: Morulae in leukocytes.

Cell tropism: Monocytes or neutrophils.

Rickettsial typhus / spotted fever

Core pathogenetic lesion: Endothelial infection.

Cellular injury leads to systemic vasculopathy.

Slide 64 · Start diagnosis with the clinical syndrome

Clinical suspicion

Acute fever, headache, rash or systemic illness

Exposure context

Lice, chigger, or tick

Discriminating features

Rash distribution, eschar, or morulae

Confirmation

Serology or organism immunostaining

Clinical diagnosis with confirmatory serology or immunostaining for rickettsial diseases.

Slide 65 · Histologic patterns should be interpreted in context

Observation

Interpretation supported by Robbins

Mononuclear perivascular cuffs

Typical typhus microvascular response

Vascular necrosis with fibrin leakage

Supports RMSF-type vasculitis

Focal microglial nodule

Characteristic brain lesion of typhus

Cytoplasmic leukocyte morulae

Supports ehrlichial or anaplasmal infection

Slide 66 · Gram staining is not a reliable exclusion tool

What it can show

The group has gram-negative bacterial structure.

Routine Gram staining may reveal little organism detail.

What else contributes

Epidemiologic and clinical pattern

Rickettsial serology or organism immunostaining

Slide 67 · A four-syndrome side-by-side diagnosis map

Illness

Vector

Rash clue

Tissue / cell clue

Epidemic typhus

Lice

Spared palms/soles

Perivascular cuff; typhus nodule

Scrub typhus

Chigger

Often absent or transient

Eschar; lymphadenopathy

RMSF

Tick

May involve palms/soles

Necrotizing small-vessel injury

Ehrlichiosis / anaplasmosis

Tick

Nonspecific / variable

Leukocyte morulae

Slide 68 · Case application: Fever following louse exposure

Illustrative teaching scenario

A patient from a crowded setting with poor hygiene has an evolving macular-to-petechial rash. Palms and soles are spared. Biopsy shows swollen small-vessel endothelium with mononuclear cuffs.

Which infection best fits, and what is the major pathologic target?

Clues to weigh

Louse-associated setting

Rash distribution

Small-vessel endothelial lesion

Slide 69 · Case interpretation: Epidemic typhus

Epidemic typhus — Rickettsia prowazekii

Louse transmission is a defining exposure clue.

Palms and soles are typically spared.

Endothelial infection explains the perivascular changes and rash.

Severe cases can progress to hemorrhage, thrombosis, and peripheral necrosis.

Slide 70 · Case application: Rash reaches the palms and soles

Illustrative teaching scenario

A patient develops fever, severe myalgias, gastrointestinal symptoms, and then a petechial eruption involving palms and soles after tick exposure.

Which illness and which tissue lesion should be anticipated?

Clues to weigh

Tick-related systemic disease

Progressing petechial rash

Palmar and plantar involvement

Slide 71 · Case interpretation: Rocky Mountain spotted fever

Rocky Mountain spotted fever — Rickettsia rickettsii

A tick-associated illness precedes an evolving petechial rash.

Palmar and plantar involvement is a characteristic clinical clue.

Small-vessel necrosis and fibrin extravasation distinguish the pathologic pattern.

Major severe complication: Noncardiogenic pulmonary edema with ARDS.

Slide 72 · Case application: Inclusions in granulocytes

Illustrative teaching scenario

A patient presents with abrupt fever, headache, and malaise following a deer-tick exposure. Blood examination shows clusters of bacterial inclusions in neutrophil cytoplasm.

Identify the likely agent and name the cytoplasmic structure.

Clues to weigh

Deer-tick exposure

Neutrophil tropism

Cytoplasmic clusters

Slide 73 · Case interpretation: Anaplasmosis

Anaplasmosis — Anaplasma phagocytophilum

Deer ticks are the source-described vector.

A. Phagocytophilum predominantly infects neutrophils.

The bacterial cytoplasmic inclusions are morulae.

Differentiate E. Chaffeensis by its monocyte tropism and lone-star-tick association.

Slide 74 · Pathogenesis synthesis: Cell compartment to organ injury

Intracellular pathogen

Replication depends on host cell

Tropism

Endothelium or leukocyte

Local lesion

Vascular damage or morula formation

Clinical phenotype

Rash, organ dysfunction, or febrile syndrome

Anatomical cell tropism creates the diagnostic logic of the group.

Slide 75 · Morphology synthesis: Recognize the discriminators

Typhus

Perivascular mononuclear cuffs; Brain nodules

RMSF

Necrotizing vascular lesions and fibrin leakage

Anaplasmosis / ehrlichiosis

Morulae within affected leukocytes

Scrub typhus additionally emphasizes eschar and regional lymphadenopathy.

Slide 76 · Final clinicopathologic distinctions

Endothelial tropism explains the vascular pathology of typhus and spotted fevers.

Rash distribution differs: Palms and soles are typically spared in epidemic typhus but may be involved in RMSF.

Scrub typhus may feature an eschar and prominent lymphadenopathy.

Leukocyte morulae identify the distinctive cellular pattern of ehrlichiosis and anaplasmosis.

Slide 77 · References

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026). Chapter 8, Infectious Diseases.

Obligate Intracellular Bacterial Infections; Infections Caused by Other Intracellular Bacteria; relevant Pathogenesis and Morphology sections.

Original textbook figures 8.40–8.42 were described in the supplied text but were not reproduced; diagrams in this lecture are newly authored schematics.